UCHL3 Data Analysis

HGNC Gene Name
ubiquitin C-terminal hydrolase L3
HGNC Gene Symbol
hgnc:12515 NCBIGene:7347 uniprot:P15374
mgi:1355274 rgd:1561196
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for UCHL3
Number of Papers
98 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
PPM1D protein phosphatase, Mg2+/Mn2+ dependent 1D 0.297 -0.15 -0.90 1.51e-01
MDM2 MDM2 proto-oncogene 0.266 Reactome (3) 0.01 -0.02 9.05e-01
COMMD6 COMM domain containing 6 0.259 Reactome (3) 0.47 2.52 4.06e-20
TP53BP1 tumor protein p53 binding protein 1 -0.253 Reactome (2) -0.42 -2.40 7.93e-16
TP53 tumor protein p53 -0.249 Reactome (3) 0.06 0.22 4.06e-01
KRTAP21-1 keratin associated protein 21-1 0.24
MDM4 MDM4 regulator of p53 0.231 Reactome (3)

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with UCHL3using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value
GO:0030330 DNA damage response, signal transduction by p53 class mediator Biological Process 1.37e-08 6.14e-06 1.63e-06
GO:0042770 signal transduction in response to DNA damage Biological Process 3.32e-08 1.49e-05 1.98e-06
GO:0031570 DNA integrity checkpoint Biological Process 6.85e-08 3.08e-05 2.72e-06
GO:0000075 cell cycle checkpoint Biological Process 2.41e-07 1.08e-04 7.16e-06
GO:0072331 signal transduction by p53 class mediator Biological Process 5.54e-07 2.49e-04 1.29e-05
GO:0002039 p53 binding Molecular Function 7.62e-07 3.42e-04 1.29e-05
GO:0071479 cellular response to ionizing radiation Biological Process 9.96e-07 4.47e-04 1.48e-05
GO:0072395 signal transduction involved in cell cycle checkpoint Biological Process 1.13e-06 5.07e-04 1.49e-05
GO:0071158 positive regulation of cell cycle arrest Biological Process 1.54e-06 6.92e-04 1.83e-05
GO:0044774 mitotic DNA integrity checkpoint Biological Process 3.44e-06 1.55e-03 3.51e-05
GO:0071156 regulation of cell cycle arrest Biological Process 3.54e-06 1.59e-03 3.51e-05
GO:0009314 response to radiation Biological Process 4.43e-06 1.99e-03 4.05e-05
GO:1902807 negative regulation of cell cycle G1/S phase transition Biological Process 6.19e-06 2.78e-03 5.26e-05
GO:0010212 response to ionizing radiation Biological Process 9.14e-06 4.10e-03 7.25e-05
GO:0007093 mitotic cell cycle checkpoint Biological Process 1.27e-05 5.69e-03 9.42e-05
GO:1901796 regulation of signal transduction by p53 class mediator Biological Process 1.62e-05 7.26e-03 1.13e-04
GO:0046827 positive regulation of protein export from nucleus Biological Process 1.75e-05 7.84e-03 1.15e-04
GO:0071478 cellular response to radiation Biological Process 1.93e-05 8.68e-03 1.21e-04
GO:0071157 negative regulation of cell cycle arrest Biological Process 2.10e-05 9.44e-03 1.25e-04
GO:1902806 regulation of cell cycle G1/S phase transition Biological Process 2.25e-05 1.01e-02 1.28e-04
GO:0071480 cellular response to gamma radiation Biological Process 3.37e-05 1.51e-02 1.82e-04
GO:0071453 cellular response to oxygen levels Biological Process 3.60e-05 1.62e-02 1.86e-04
GO:0007050 cell cycle arrest Biological Process 4.08e-05 1.83e-02 1.96e-04
GO:0097718 disordered domain specific binding Molecular Function 4.12e-05 1.85e-02 1.96e-04
GO:1901988 negative regulation of cell cycle phase transition Biological Process 5.22e-05 2.34e-02 2.33e-04
GO:0031668 cellular response to extracellular stimulus Biological Process 5.28e-05 2.37e-02 2.33e-04
GO:0046825 regulation of protein export from nucleus Biological Process 6.47e-05 2.90e-02 2.75e-04
GO:0044843 cell cycle G1/S phase transition Biological Process 7.04e-05 3.16e-02 2.87e-04
GO:0090068 positive regulation of cell cycle process Biological Process 7.33e-05 3.29e-02 2.87e-04
GO:0070646 protein modification by small protein removal Biological Process 7.48e-05 3.36e-02 2.87e-04
GO:0071214 cellular response to abiotic stimulus Biological Process 9.32e-05 4.19e-02 3.47e-04
GO:0071496 cellular response to external stimulus Biological Process 1.05e-04 4.71e-02 3.67e-04
GO:0045930 negative regulation of mitotic cell cycle Biological Process 1.05e-04 4.71e-02 3.67e-04


The following table shows the significantly differentially expressed genes after knocking out UCHL3 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
UCHL3 ubiquitin C-terminal hydrolase L3 -1.06e+00 6.55e-13 3.53e-09
SMARCA5 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5 8.69e-01 1.44e-07 2.78e-04
TPM4 tropomyosin 4 4.71e-01 1.55e-07 2.78e-04
PTBP1 polypyrimidine tract binding protein 1 9.60e-01 3.08e-07 4.15e-04
YBX1 Y-box binding protein 1 5.89e-01 5.02e-07 5.40e-04
HNRNPAB heterogeneous nuclear ribonucleoprotein A/B 6.66e-01 6.65e-07 5.96e-04
CEP55 centrosomal protein 55 9.11e-01 1.31e-06 1.01e-03
SUPT6H SPT6 homolog, histone chaperone and transcription elongation factor 7.42e-01 1.50e-06 1.01e-03
BAP1 BRCA1 associated protein 1 -6.93e-01 3.14e-06 1.86e-03
CENPF centromere protein F 4.71e-01 3.46e-06 1.86e-03
CKAP5 cytoskeleton associated protein 5 5.94e-01 5.46e-06 2.67e-03
TCHP trichoplein keratin filament binding 5.67e-01 9.25e-06 4.15e-03
IQGAP1 IQ motif containing GTPase activating protein 1 6.79e-01 1.03e-05 4.27e-03
SPTBN1 spectrin beta, non-erythrocytic 1 4.96e-01 1.33e-05 5.10e-03
ANP32A acidic nuclear phosphoprotein 32 family member A 7.54e-01 1.45e-05 5.21e-03
TPM3 tropomyosin 3 4.40e-01 2.18e-05 7.32e-03
SHCBP1 SHC binding and spindle associated 1 8.39e-01 2.45e-05 7.75e-03
SENP7 SUMO specific peptidase 7 -6.76e-01 2.99e-05 8.48e-03
TAF15 TATA-box binding protein associated factor 15 7.10e-01 2.92e-05 8.48e-03
HDGF heparin binding growth factor 5.45e-01 3.93e-05 1.06e-02
ARHGAP35 Rho GTPase activating protein 35 6.99e-01 5.13e-05 1.12e-02
EZR ezrin 4.01e-01 5.20e-05 1.12e-02
GOLGB1 golgin B1 6.63e-01 5.00e-05 1.12e-02
NABP1 nucleic acid binding protein 1 -3.61e-01 4.58e-05 1.12e-02
PJA2 praja ring finger ubiquitin ligase 2 7.37e-01 5.63e-05 1.17e-02
BEX3 brain expressed X-linked 3 -2.67e-01 6.08e-05 1.21e-02
CD59 CD59 molecule (CD59 blood group) -3.51e-01 7.20e-05 1.36e-02
IGFBP4 insulin like growth factor binding protein 4 -3.32e-01 7.31e-05 1.36e-02
EPB41L2 erythrocyte membrane protein band 4.1 like 2 7.05e-01 8.03e-05 1.44e-02
EIF3C eukaryotic translation initiation factor 3 subunit C 5.05e-01 9.17e-05 1.59e-02
YIPF4 Yip1 domain family member 4 4.48e-01 1.30e-04 2.18e-02
MSN moesin 5.15e-01 1.47e-04 2.40e-02
DENR density regulated re-initiation and release factor 4.13e-01 1.61e-04 2.48e-02
MIA3 MIA SH3 domain ER export factor 3 5.82e-01 1.61e-04 2.48e-02
FTH1 ferritin heavy chain 1 4.58e-01 1.81e-04 2.51e-02
NOL7 nucleolar protein 7 3.94e-01 1.73e-04 2.51e-02
SMC1A structural maintenance of chromosomes 1A 4.79e-01 1.82e-04 2.51e-02
TOP1 DNA topoisomerase I 4.86e-01 1.81e-04 2.51e-02
C15orf48 chromosome 15 open reading frame 48 -5.71e-01 2.04e-04 2.63e-02
ENAH ENAH actin regulator 6.82e-01 2.09e-04 2.63e-02
HS3ST1 heparan sulfate-glucosamine 3-sulfotransferase 1 -3.33e-01 2.15e-04 2.63e-02
NDUFB5 NADH:ubiquinone oxidoreductase subunit B5 -4.52e-01 2.15e-04 2.63e-02
PPM1G protein phosphatase, Mg2+/Mn2+ dependent 1G 4.00e-01 2.06e-04 2.63e-02
HNRNPA2B1 heterogeneous nuclear ribonucleoprotein A2/B1 2.46e-01 2.24e-04 2.68e-02
PDAP1 PDGFA associated protein 1 4.71e-01 2.46e-04 2.77e-02
SRP72 signal recognition particle 72 4.40e-01 2.38e-04 2.77e-02
WDR3 WD repeat domain 3 6.27e-01 2.47e-04 2.77e-02
AKAP12 A-kinase anchoring protein 12 6.44e-01 2.60e-04 2.86e-02
EIF4B eukaryotic translation initiation factor 4B 5.35e-01 2.99e-04 3.22e-02
CAB39 calcium binding protein 39 6.02e-01 3.20e-04 3.31e-02
NCL nucleolin 3.99e-01 3.19e-04 3.31e-02
CEP250 centrosomal protein 250 4.95e-01 3.28e-04 3.33e-02
MTCO2P2 MT-CO2 pseudogene 2 -5.03e-01 3.48e-04 3.37e-02
MYH9 myosin heavy chain 9 4.47e-01 3.55e-04 3.37e-02
EPRS1 glutamyl-prolyl-tRNA synthetase 1 -4.94e-01 3.45e-04 3.37e-02
RBSN rabenosyn, RAB effector 6.81e-01 3.57e-04 3.37e-02
MT-CO2 mitochondrially encoded cytochrome c oxidase II -2.23e-01 3.84e-04 3.57e-02
DSP desmoplakin 6.32e-01 4.24e-04 3.82e-02
LRRC69 leucine rich repeat containing 69 1.91e-01 4.26e-04 3.82e-02
NRDC nardilysin convertase 5.20e-01 4.53e-04 4.00e-02
GBP1P1 guanylate binding protein 1 pseudogene 1 -5.14e-01 5.07e-04 4.36e-02
HNRNPD heterogeneous nuclear ribonucleoprotein D 4.64e-01 5.11e-04 4.36e-02
NIPBL NIPBL cohesin loading factor 6.29e-01 5.41e-04 4.48e-02
SSR2 signal sequence receptor subunit 2 -2.97e-01 5.39e-04 4.48e-02
AHNAK AHNAK nucleoprotein 5.86e-01 5.71e-04 4.59e-02
ZMYND8 zinc finger MYND-type containing 8 5.09e-01 5.67e-04 4.59e-02
BNIP3 BCL2 interacting protein 3 -4.10e-01 6.90e-04 4.84e-02
CAPN7 calpain 7 7.19e-01 6.84e-04 4.84e-02
FCF1 FCF1 rRNA-processing protein 5.67e-01 6.47e-04 4.84e-02
IFI16 interferon gamma inducible protein 16 5.22e-01 6.56e-04 4.84e-02
NDC1 NDC1 transmembrane nucleoporin 6.03e-01 6.92e-04 4.84e-02
NOP14 NOP14 nucleolar protein 5.90e-01 6.73e-04 4.84e-02
R3HDM1 R3H domain containing 1 6.15e-01 6.36e-04 4.84e-02
SMARCC1 SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1 5.67e-01 6.86e-04 4.84e-02
SMIM15 small integral membrane protein 15 5.55e-01 6.38e-04 4.84e-02
SYAP1 synapse associated protein 1 4.16e-01 6.54e-04 4.84e-02
CHMP4B charged multivesicular body protein 4B 6.76e-01 7.16e-04 4.94e-02

Gene Set Enrichment Analysis

The GSEA method was applied for all genes whose knockout resulted in at least 20 significantly differentially expressed genes.

ID Name p-value p-value (adj.) log2 Error ES NES
msig:M5893 HALLMARK_MITOTIC_SPINDLE 2.11e-09 3.76e-06 7.75e-01 5.20e-01 2.17e+00
go:0008092 cytoskeletal protein binding 1.28e-09 3.76e-06 7.88e-01 4.09e-01 1.90e+00
go:0007010 cytoskeleton organization 3.19e-09 3.80e-06 7.75e-01 3.75e-01 1.78e+00
go:0019904 protein domain specific binding 5.14e-08 4.58e-05 7.20e-01 4.07e-01 1.86e+00
go:0030554 adenyl nucleotide binding 2.42e-07 1.73e-04 6.75e-01 3.44e-01 1.66e+00
go:0050839 cell adhesion molecule binding 3.12e-07 1.86e-04 6.75e-01 4.02e-01 1.83e+00
go:0032553 ribonucleotide binding 5.51e-07 2.81e-04 6.59e-01 3.23e-01 1.57e+00
go:0042393 histone binding 7.30e-07 3.21e-04 6.59e-01 5.04e-01 2.04e+00
go:0003682 chromatin binding 9.91e-07 3.21e-04 6.44e-01 4.02e-01 1.80e+00
go:0015630 microtubule cytoskeleton 9.33e-07 3.21e-04 6.59e-01 3.39e-01 1.62e+00
go:0006091 generation of precursor metabolites and energy 8.66e-07 3.21e-04 6.59e-01 -3.29e-01 -1.75e+00
go:0044429 1.14e-06 3.39e-04 6.44e-01 -2.65e-01 -1.51e+00
go:0044430 1.55e-06 4.24e-04 6.44e-01 3.25e-01 1.57e+00
go:0010628 positive regulation of gene expression 1.95e-06 4.63e-04 6.27e-01 3.19e-01 1.55e+00
go:0045296 cadherin binding 2.31e-06 5.15e-04 6.27e-01 4.04e-01 1.80e+00
go:0008144 drug binding 2.88e-06 5.70e-04 6.27e-01 3.19e-01 1.54e+00
go:0051276 chromosome organization 3.62e-06 6.46e-04 6.27e-01 3.24e-01 1.56e+00
go:0098590 plasma membrane region 5.13e-06 8.71e-04 6.11e-01 3.87e-01 1.74e+00
go:0033043 regulation of organelle organization 5.78e-06 8.97e-04 6.11e-01 3.20e-01 1.54e+00
go:0015631 tubulin binding 5.61e-06 8.97e-04 6.11e-01 4.45e-01 1.87e+00
go:0044877 protein-containing complex binding 6.97e-06 9.56e-04 6.11e-01 3.40e-01 1.61e+00
go:0098800 inner mitochondrial membrane protein complex 6.97e-06 9.56e-04 6.11e-01 -4.09e-01 -1.90e+00
go:0030029 actin filament-based process 6.67e-06 9.56e-04 6.11e-01 3.77e-01 1.69e+00
go:0000226 microtubule cytoskeleton organization 7.67e-06 9.77e-04 5.93e-01 3.88e-01 1.74e+00
go:0003779 actin binding 7.55e-06 9.77e-04 6.11e-01 4.31e-01 1.84e+00
go:0019900 kinase binding 8.91e-06 1.10e-03 5.93e-01 3.65e-01 1.67e+00
go:0099080 supramolecular complex 9.72e-06 1.12e-03 5.93e-01 3.76e-01 1.72e+00
go:0007017 microtubule-based process 9.58e-06 1.12e-03 5.93e-01 3.60e-01 1.66e+00
go:0005815 microtubule organizing center 1.01e-05 1.13e-03 5.93e-01 3.57e-01 1.65e+00
go:0009891 positive regulation of biosynthetic process 1.13e-05 1.22e-03 5.93e-01 3.08e-01 1.49e+00
go:0051493 regulation of cytoskeleton organization 1.26e-05 1.32e-03 5.93e-01 3.99e-01 1.77e+00
go:0022900 electron transport chain 1.31e-05 1.33e-03 5.93e-01 -3.76e-01 -1.79e+00
go:0022402 cell cycle process 1.66e-05 1.64e-03 5.76e-01 3.07e-01 1.49e+00
go:0030030 cell projection organization 1.83e-05 1.76e-03 5.76e-01 3.31e-01 1.57e+00
go:0097435 supramolecular fiber organization 1.94e-05 1.82e-03 5.76e-01 3.82e-01 1.71e+00
go:0032990 cell part morphogenesis 2.25e-05 2.05e-03 5.76e-01 4.10e-01 1.79e+00
go:0030182 neuron differentiation 2.50e-05 2.12e-03 5.76e-01 3.49e-01 1.62e+00
go:0031399 regulation of protein modification process 2.49e-05 2.12e-03 5.76e-01 3.11e-01 1.51e+00
go:0048589 developmental growth 2.50e-05 2.12e-03 5.76e-01 3.94e-01 1.74e+00
go:0022008 neurogenesis 3.04e-05 2.50e-03 5.76e-01 3.30e-01 1.55e+00
go:0032989 cellular component morphogenesis 3.09e-05 2.50e-03 5.57e-01 3.52e-01 1.62e+00
go:0006119 oxidative phosphorylation 3.41e-05 2.61e-03 5.57e-01 -3.77e-01 -1.75e+00
go:0019866 organelle inner membrane 3.44e-05 2.61e-03 5.57e-01 -2.81e-01 -1.52e+00
go:0016887 ATPase activity 3.57e-05 2.62e-03 5.57e-01 3.94e-01 1.74e+00
go:0003690 double-stranded DNA binding 3.60e-05 2.62e-03 5.57e-01 3.56e-01 1.63e+00
go:0009890 negative regulation of biosynthetic process 3.79e-05 2.70e-03 5.57e-01 3.18e-01 1.53e+00
go:0071103 DNA conformation change 3.99e-05 2.74e-03 5.57e-01 4.16e-01 1.77e+00
reactome:R-HSA-1428517 The citric acid (TCA) cycle and respiratory electron transport 3.96e-05 2.74e-03 5.57e-01 -3.58e-01 -1.72e+00
go:0044455 4.46e-05 2.84e-03 5.57e-01 -3.39e-01 -1.69e+00
go:0099568 cytoplasmic region 4.45e-05 2.84e-03 5.57e-01 4.03e-01 1.76e+00
go:0050684 regulation of mRNA processing 4.56e-05 2.85e-03 5.57e-01 4.59e-01 1.86e+00
go:0007051 spindle organization 5.10e-05 3.08e-03 5.57e-01 4.55e-01 1.84e+00
go:0004386 helicase activity 5.03e-05 3.08e-03 5.57e-01 4.73e-01 1.87e+00
go:0005740 mitochondrial envelope 5.70e-05 3.39e-03 5.57e-01 -2.64e-01 -1.45e+00
go:0000122 negative regulation of transcription by RNA polymerase II 5.94e-05 3.48e-03 5.57e-01 3.59e-01 1.64e+00
go:0005694 chromosome 6.14e-05 3.53e-03 5.38e-01 3.12e-01 1.50e+00
go:0033044 regulation of chromosome organization 6.97e-05 3.71e-03 5.38e-01 3.87e-01 1.71e+00
go:0022904 respiratory electron transport chain 6.75e-05 3.71e-03 5.38e-01 -3.99e-01 -1.82e+00
go:0016604 nuclear body 6.88e-05 3.71e-03 5.38e-01 3.29e-01 1.54e+00
go:0010564 regulation of cell cycle process 6.88e-05 3.71e-03 5.38e-01 3.24e-01 1.52e+00
go:0008094 DNA-dependent ATPase activity 6.69e-05 3.71e-03 5.38e-01 5.32e-01 1.94e+00
go:0008017 microtubule binding 7.40e-05 3.88e-03 5.38e-01 4.52e-01 1.83e+00
go:0061061 muscle structure development 8.22e-05 4.19e-03 5.38e-01 3.87e-01 1.70e+00
go:0015980 energy derivation by oxidation of organic compounds 8.18e-05 4.19e-03 5.38e-01 -3.30e-01 -1.64e+00
go:0051174 regulation of phosphorus metabolic process 9.24e-05 4.58e-03 5.38e-01 3.08e-01 1.48e+00
go:0043565 sequence-specific DNA binding 9.19e-05 4.58e-03 5.38e-01 3.51e-01 1.61e+00
go:0030496 midbody 9.49e-05 4.64e-03 5.38e-01 4.39e-01 1.80e+00
go:0030054 cell junction 1.09e-04 5.23e-03 5.38e-01 3.18e-01 1.51e+00
go:0007507 heart development 1.18e-04 5.59e-03 5.38e-01 3.97e-01 1.72e+00
go:0051056 regulation of small GTPase mediated signal transduction 1.27e-04 5.84e-03 5.19e-01 4.58e-01 1.84e+00
go:0005819 spindle 1.25e-04 5.84e-03 5.19e-01 3.82e-01 1.69e+00
go:0045944 positive regulation of transcription by RNA polymerase II 1.28e-04 5.84e-03 5.19e-01 3.31e-01 1.54e+00
go:0010562 positive regulation of phosphorus metabolic process 1.39e-04 6.28e-03 5.19e-01 3.37e-01 1.56e+00
go:0043583 ear development 1.43e-04 6.29e-03 5.19e-01 5.55e-01 1.96e+00
go:0098803 respiratory chain complex 1.53e-04 6.65e-03 5.19e-01 -4.22e-01 -1.85e+00
go:0045333 cellular respiration 1.59e-04 6.73e-03 5.19e-01 -3.53e-01 -1.70e+00
go:0004672 protein kinase activity 1.57e-04 6.73e-03 5.19e-01 3.88e-01 1.70e+00
go:0030048 actin filament-based movement 1.71e-04 7.19e-03 5.19e-01 5.71e-01 1.96e+00
go:0034728 nucleosome organization 1.77e-04 7.26e-03 5.19e-01 4.85e-01 1.87e+00
go:0005813 centrosome 1.77e-04 7.26e-03 5.19e-01 3.51e-01 1.58e+00
go:0000910 cytokinesis 1.80e-04 7.28e-03 5.19e-01 4.62e-01 1.83e+00
go:0099513 polymeric cytoskeletal fiber 1.84e-04 7.37e-03 5.19e-01 3.55e-01 1.60e+00
go:0044093 positive regulation of molecular function 1.91e-04 7.49e-03 5.19e-01 2.99e-01 1.45e+00
go:0005759 mitochondrial matrix 1.96e-04 7.50e-03 5.19e-01 -2.82e-01 -1.50e+00
go:0051640 organelle localization 1.95e-04 7.50e-03 5.19e-01 3.41e-01 1.56e+00
go:0061028 establishment of endothelial barrier 2.11e-04 7.82e-03 5.19e-01 6.99e-01 2.01e+00
go:0005938 cell cortex 2.11e-04 7.82e-03 5.19e-01 4.19e-01 1.74e+00
go:0070997 neuron death 2.16e-04 7.87e-03 5.19e-01 4.07e-01 1.70e+00
go:0070469 respirasome 2.24e-04 8.07e-03 5.19e-01 -3.99e-01 -1.78e+00
go:0048666 neuron development 2.74e-04 9.78e-03 4.98e-01 3.38e-01 1.55e+00
go:0048667 cell morphogenesis involved in neuron differentiation 2.81e-04 9.87e-03 4.98e-01 3.96e-01 1.68e+00
go:0008134 transcription factor binding 2.82e-04 9.87e-03 4.98e-01 3.41e-01 1.55e+00
reactome:R-HSA-73884 Base Excision Repair 2.93e-04 1.01e-02 4.98e-01 -5.21e-01 -1.97e+00
go:0031346 positive regulation of cell projection organization 2.94e-04 1.01e-02 4.98e-01 4.12e-01 1.71e+00
go:0070603 SWI/SNF superfamily-type complex 3.12e-04 1.06e-02 4.98e-01 5.30e-01 1.89e+00
go:0045595 regulation of cell differentiation 3.23e-04 1.08e-02 4.98e-01 3.01e-01 1.44e+00
go:0051656 establishment of organelle localization 3.20e-04 1.08e-02 4.98e-01 3.61e-01 1.60e+00
go:0045664 regulation of neuron differentiation 3.41e-04 1.09e-02 4.98e-01 3.88e-01 1.68e+00
go:0042773 ATP synthesis coupled electron transport 3.39e-04 1.09e-02 4.98e-01 -3.93e-01 -1.75e+00
go:0000904 cell morphogenesis involved in differentiation 3.36e-04 1.09e-02 4.98e-01 3.65e-01 1.62e+00
go:0003700 DNA-binding transcription factor activity 3.41e-04 1.09e-02 4.98e-01 3.19e-01 1.48e+00
go:0006325 chromatin organization 3.47e-04 1.09e-02 4.98e-01 3.23e-01 1.50e+00
go:0000785 chromatin 3.44e-04 1.09e-02 4.98e-01 3.40e-01 1.53e+00
go:0040011 locomotion 3.49e-04 1.09e-02 4.98e-01 3.00e-01 1.43e+00
go:0016607 nuclear speck 3.75e-04 1.15e-02 4.98e-01 3.45e-01 1.54e+00
reactome:R-HSA-75153 Apoptotic execution phase 3.75e-04 1.15e-02 4.98e-01 5.90e-01 1.94e+00
go:0007163 establishment or maintenance of cell polarity 3.92e-04 1.16e-02 4.98e-01 4.50e-01 1.78e+00
reactome:R-HSA-5689603 UCH proteinases 3.93e-04 1.16e-02 4.98e-01 -4.15e-01 -1.81e+00
go:0006468 protein phosphorylation 3.89e-04 1.16e-02 4.98e-01 2.89e-01 1.40e+00
msig:M7272 KEGG_PARKINSONS_DISEASE 3.82e-04 1.16e-02 4.98e-01 -3.74e-01 -1.72e+00
reactome:R-HSA-163200 Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins. 4.11e-04 1.20e-02 4.98e-01 -3.60e-01 -1.67e+00
go:0099177 regulation of trans-synaptic signaling 4.14e-04 1.20e-02 4.98e-01 4.47e-01 1.76e+00
go:0060284 regulation of cell development 4.22e-04 1.20e-02 4.98e-01 3.41e-01 1.54e+00
msig:M5934 HALLMARK_XENOBIOTIC_METABOLISM 4.25e-04 1.20e-02 4.98e-01 -3.96e-01 -1.76e+00
go:1990266 neutrophil migration 4.23e-04 1.20e-02 4.98e-01 -6.71e-01 -2.07e+00
go:0097060 synaptic membrane 4.48e-04 1.25e-02 4.98e-01 5.00e-01 1.84e+00
go:0051018 protein kinase A binding 4.47e-04 1.25e-02 4.98e-01 7.07e-01 1.98e+00
go:0051960 regulation of nervous system development 4.86e-04 1.34e-02 4.98e-01 3.48e-01 1.56e+00
go:0006338 chromatin remodeling 4.96e-04 1.36e-02 4.77e-01 4.31e-01 1.73e+00
reactome:R-HSA-1500931 Cell-Cell communication 5.15e-04 1.39e-02 4.77e-01 5.41e-01 1.88e+00
go:0035064 methylated histone binding 5.15e-04 1.39e-02 4.77e-01 6.09e-01 1.95e+00
go:0003725 double-stranded RNA binding 5.24e-04 1.40e-02 4.77e-01 5.22e-01 1.86e+00
go:0070161 anchoring junction 5.28e-04 1.40e-02 4.77e-01 3.28e-01 1.51e+00
go:0016071 mRNA metabolic process 5.33e-04 1.40e-02 4.77e-01 3.17e-01 1.48e+00
go:0051983 regulation of chromosome segregation 5.36e-04 1.40e-02 4.77e-01 4.57e-01 1.78e+00
go:0005884 actin filament 5.89e-04 1.53e-02 4.77e-01 5.63e-01 1.87e+00
reactome:R-HSA-5696397 Gap-filling DNA repair synthesis and ligation in GG-NER 6.42e-04 1.66e-02 4.77e-01 -6.34e-01 -2.01e+00
go:0051347 positive regulation of transferase activity 6.58e-04 1.69e-02 4.77e-01 3.49e-01 1.57e+00
go:0046847 filopodium assembly 6.64e-04 1.69e-02 4.77e-01 6.67e-01 1.95e+00
go:0044282 small molecule catabolic process 6.70e-04 1.70e-02 4.77e-01 -3.32e-01 -1.54e+00
go:0044087 regulation of cellular component biogenesis 6.86e-04 1.72e-02 4.77e-01 3.15e-01 1.46e+00
go:0005516 calmodulin binding 6.97e-04 1.74e-02 4.77e-01 5.06e-01 1.84e+00
reactome:R-HSA-611105 Respiratory electron transport 7.20e-04 1.78e-02 4.77e-01 -3.80e-01 -1.70e+00
go:0031252 cell leading edge 7.31e-04 1.80e-02 4.77e-01 3.76e-01 1.60e+00
go:0007423 sensory organ development 7.40e-04 1.81e-02 4.77e-01 4.03e-01 1.67e+00
go:0001885 endothelial cell development 7.67e-04 1.86e-02 4.77e-01 6.25e-01 1.95e+00
go:0072359 circulatory system development 7.80e-04 1.88e-02 4.77e-01 3.25e-01 1.49e+00
go:0098813 nuclear chromosome segregation 8.03e-04 1.92e-02 4.77e-01 3.74e-01 1.59e+00
go:0090068 positive regulation of cell cycle process 8.15e-04 1.92e-02 4.77e-01 3.79e-01 1.61e+00
go:0032886 regulation of microtubule-based process 8.12e-04 1.92e-02 4.77e-01 4.14e-01 1.67e+00
go:0090224 regulation of spindle organization 8.32e-04 1.95e-02 4.77e-01 6.08e-01 1.91e+00
go:0080135 regulation of cellular response to stress 8.77e-04 2.03e-02 4.77e-01 3.24e-01 1.49e+00
go:0031401 positive regulation of protein modification process 9.40e-04 2.14e-02 4.77e-01 3.07e-01 1.44e+00
reactome:R-HSA-157579 Telomere Maintenance 9.50e-04 2.14e-02 4.77e-01 -5.18e-01 -1.91e+00
go:0030055 cell-substrate junction 9.62e-04 2.16e-02 4.77e-01 3.27e-01 1.47e+00
go:0045202 synapse 9.88e-04 2.20e-02 4.55e-01 3.22e-01 1.49e+00
go:0022610 biological adhesion 1.01e-03 2.24e-02 4.55e-01 3.08e-01 1.44e+00
go:0048167 regulation of synaptic plasticity 1.02e-03 2.25e-02 4.55e-01 5.49e-01 1.83e+00
go:0044242 cellular lipid catabolic process 1.03e-03 2.26e-02 4.55e-01 -4.12e-01 -1.73e+00
go:0043085 positive regulation of catalytic activity 1.04e-03 2.26e-02 4.55e-01 2.94e-01 1.40e+00
go:0050918 positive chemotaxis 1.05e-03 2.26e-02 4.55e-01 -6.47e-01 -1.99e+00
go:0051726 regulation of cell cycle 1.07e-03 2.29e-02 4.55e-01 2.88e-01 1.39e+00
go:0007059 chromosome segregation 1.07e-03 2.29e-02 4.55e-01 3.60e-01 1.58e+00
go:0051236 establishment of RNA localization 1.08e-03 2.29e-02 4.55e-01 3.81e-01 1.61e+00
go:0032506 cytokinetic process 1.13e-03 2.39e-02 4.55e-01 5.82e-01 1.84e+00
go:0051233 spindle midzone 1.16e-03 2.41e-02 4.55e-01 6.20e-01 1.88e+00
go:0005911 cell-cell junction 1.15e-03 2.41e-02 4.55e-01 3.84e-01 1.63e+00
go:0016052 carbohydrate catabolic process 1.21e-03 2.50e-02 4.55e-01 -3.89e-01 -1.70e+00
go:0051338 regulation of transferase activity 1.24e-03 2.55e-02 4.55e-01 3.07e-01 1.43e+00
go:0032970 regulation of actin filament-based process 1.25e-03 2.57e-02 4.55e-01 3.78e-01 1.60e+00
go:0000922 spindle pole 1.27e-03 2.59e-02 4.55e-01 4.20e-01 1.68e+00
go:1901215 negative regulation of neuron death 1.29e-03 2.61e-02 4.55e-01 4.48e-01 1.73e+00
go:0000278 mitotic cell cycle 1.31e-03 2.62e-02 4.55e-01 2.93e-01 1.40e+00
go:0061564 axon development 1.31e-03 2.62e-02 4.55e-01 3.95e-01 1.65e+00
go:0044309 neuron spine 1.34e-03 2.67e-02 4.55e-01 4.97e-01 1.79e+00
go:0044380 protein localization to cytoskeleton 1.39e-03 2.76e-02 4.55e-01 6.19e-01 1.89e+00
go:1904949 ATPase complex 1.43e-03 2.80e-02 4.55e-01 4.80e-01 1.75e+00
go:0010975 regulation of neuron projection development 1.44e-03 2.80e-02 4.55e-01 3.85e-01 1.61e+00
go:0006275 regulation of DNA replication 1.43e-03 2.80e-02 4.55e-01 4.81e-01 1.76e+00
go:0097485 neuron projection guidance 1.46e-03 2.81e-02 4.55e-01 4.79e-01 1.75e+00
go:0098796 membrane protein complex 1.46e-03 2.81e-02 4.55e-01 -2.40e-01 -1.33e+00
reactome:R-HSA-8941858 Regulation of RUNX3 expression and activity 1.47e-03 2.81e-02 4.55e-01 -4.57e-01 -1.80e+00
go:0048515 spermatid differentiation 1.49e-03 2.83e-02 4.55e-01 5.80e-01 1.85e+00
go:0008194 UDP-glycosyltransferase activity 1.49e-03 2.83e-02 4.55e-01 -5.34e-01 -1.89e+00
go:0031491 nucleosome binding 1.52e-03 2.86e-02 4.55e-01 4.95e-01 1.77e+00
go:0015629 actin cytoskeleton 1.53e-03 2.87e-02 4.55e-01 3.50e-01 1.54e+00
go:0004674 protein serine/threonine kinase activity 1.58e-03 2.94e-02 4.55e-01 3.75e-01 1.59e+00
go:0000018 regulation of DNA recombination 1.61e-03 2.97e-02 4.55e-01 5.15e-01 1.78e+00
go:0016817 hydrolase activity, acting on acid anhydrides 1.60e-03 2.97e-02 4.55e-01 3.03e-01 1.42e+00
go:0045787 positive regulation of cell cycle 1.64e-03 3.01e-02 4.55e-01 3.47e-01 1.52e+00
go:0060148 positive regulation of posttranscriptional gene silencing 1.68e-03 3.08e-02 4.55e-01 6.68e-01 1.81e+00
go:1902850 microtubule cytoskeleton organization involved in mitosis 1.72e-03 3.14e-02 4.55e-01 4.34e-01 1.69e+00
go:0035264 multicellular organism growth 1.77e-03 3.20e-02 4.55e-01 5.00e-01 1.78e+00
go:0006297 nucleotide-excision repair, DNA gap filling 1.79e-03 3.22e-02 4.55e-01 -6.34e-01 -1.95e+00
msig:M19540 KEGG_OXIDATIVE_PHOSPHORYLATION 1.87e-03 3.33e-02 4.55e-01 -3.43e-01 -1.59e+00
go:0005739 mitochondrion 1.86e-03 3.33e-02 4.55e-01 -2.12e-01 -1.22e+00
go:0007169 transmembrane receptor protein tyrosine kinase signaling pathway 1.89e-03 3.35e-02 4.55e-01 3.25e-01 1.46e+00
go:0030010 establishment of cell polarity 1.96e-03 3.40e-02 4.32e-01 4.83e-01 1.76e+00
go:0045211 postsynaptic membrane 1.95e-03 3.40e-02 4.55e-01 5.31e-01 1.78e+00
go:0051962 positive regulation of nervous system development 1.95e-03 3.40e-02 4.55e-01 3.62e-01 1.54e+00
go:1990752 microtubule end 2.00e-03 3.41e-02 4.32e-01 6.69e-01 1.87e+00
go:0006403 RNA localization 1.98e-03 3.41e-02 4.32e-01 3.66e-01 1.59e+00
go:0042471 ear morphogenesis 1.97e-03 3.41e-02 4.32e-01 6.24e-01 1.89e+00
go:0046578 regulation of Ras protein signal transduction 1.99e-03 3.41e-02 4.32e-01 4.60e-01 1.74e+00
go:0051052 regulation of DNA metabolic process 2.01e-03 3.41e-02 4.32e-01 3.66e-01 1.55e+00
msig:M5901 HALLMARK_G2M_CHECKPOINT 2.23e-03 3.72e-02 4.32e-01 3.61e-01 1.55e+00
go:0051402 neuron apoptotic process 2.23e-03 3.72e-02 4.32e-01 4.11e-01 1.64e+00
go:0090066 regulation of anatomical structure size 2.21e-03 3.72e-02 4.32e-01 3.64e-01 1.56e+00
msig:M18306 KEGG_REGULATION_OF_ACTIN_CYTOSKELETON 2.26e-03 3.75e-02 4.32e-01 4.16e-01 1.65e+00
go:0031344 regulation of cell projection organization 2.35e-03 3.86e-02 4.32e-01 3.47e-01 1.53e+00
go:0040007 growth 2.42e-03 3.96e-02 4.32e-01 3.11e-01 1.44e+00
go:1902531 regulation of intracellular signal transduction 2.45e-03 3.97e-02 4.32e-01 2.76e-01 1.33e+00
msig:M9809 KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION 2.46e-03 3.97e-02 4.32e-01 -4.92e-01 -1.81e+00
go:0003006 developmental process involved in reproduction 2.46e-03 3.97e-02 4.32e-01 3.42e-01 1.50e+00
go:0016042 lipid catabolic process 2.48e-03 3.98e-02 4.32e-01 -3.60e-01 -1.59e+00
go:0071407 cellular response to organic cyclic compound 2.56e-03 4.10e-02 4.32e-01 3.39e-01 1.49e+00
go:0030865 cortical cytoskeleton organization 2.61e-03 4.15e-02 4.32e-01 5.95e-01 1.81e+00
go:2000779 regulation of double-strand break repair 2.65e-03 4.16e-02 4.32e-01 5.43e-01 1.79e+00
go:0008088 axo-dendritic transport 2.65e-03 4.16e-02 4.32e-01 5.37e-01 1.75e+00
reactome:R-HSA-5619115 Disorders of transmembrane transporters 2.64e-03 4.16e-02 4.32e-01 -3.53e-01 -1.57e+00
go:0006405 RNA export from nucleus 2.66e-03 4.16e-02 4.32e-01 3.85e-01 1.58e+00
go:0060324 face development 2.81e-03 4.38e-02 4.32e-01 6.30e-01 1.84e+00
go:0016757 transferase activity, transferring glycosyl groups 2.85e-03 4.42e-02 4.32e-01 -3.74e-01 -1.63e+00
go:1901224 positive regulation of NIK/NF-kappaB signaling 2.91e-03 4.49e-02 4.32e-01 5.77e-01 1.82e+00
go:0043292 contractile fiber 2.94e-03 4.52e-02 4.32e-01 4.32e-01 1.66e+00
go:0042391 regulation of membrane potential 2.96e-03 4.53e-02 4.32e-01 4.08e-01 1.63e+00
go:0140030 modification-dependent protein binding 2.99e-03 4.54e-02 4.32e-01 4.52e-01 1.71e+00
go:0043547 positive regulation of GTPase activity 2.98e-03 4.54e-02 4.32e-01 3.86e-01 1.59e+00
msig:M5936 HALLMARK_OXIDATIVE_PHOSPHORYLATION 3.01e-03 4.55e-02 4.32e-01 -2.87e-01 -1.43e+00
go:0010976 positive regulation of neuron projection development 3.09e-03 4.66e-02 4.32e-01 4.31e-01 1.70e+00
reactome:R-HSA-70268 Pyruvate metabolism 3.16e-03 4.74e-02 4.32e-01 -6.17e-01 -1.87e+00
go:0051247 positive regulation of protein metabolic process 3.21e-03 4.77e-02 4.32e-01 2.78e-01 1.34e+00
go:0045666 positive regulation of neuron differentiation 3.21e-03 4.77e-02 4.32e-01 3.94e-01 1.59e+00
go:2000781 positive regulation of double-strand break repair 3.22e-03 4.77e-02 4.32e-01 6.53e-01 1.77e+00
go:1990204 oxidoreductase complex 3.29e-03 4.84e-02 4.32e-01 -3.64e-01 -1.63e+00
go:0120034 positive regulation of plasma membrane bounded cell projection assembly 3.44e-03 5.05e-02 4.32e-01 5.24e-01 1.72e+00
go:0098794 postsynapse 3.47e-03 5.05e-02 4.32e-01 3.58e-01 1.54e+00
go:0032467 positive regulation of cytokinesis 3.49e-03 5.05e-02 4.32e-01 6.28e-01 1.77e+00
go:0048646 anatomical structure formation involved in morphogenesis 3.50e-03 5.05e-02 4.32e-01 3.14e-01 1.43e+00
go:0030595 leukocyte chemotaxis 3.52e-03 5.06e-02 4.32e-01 -4.29e-01 -1.68e+00
go:0044463 3.57e-03 5.10e-02 4.32e-01 2.92e-01 1.37e+00
go:0002064 epithelial cell development 3.62e-03 5.14e-02 4.32e-01 4.20e-01 1.64e+00
go:1902275 regulation of chromatin organization 3.65e-03 5.16e-02 4.32e-01 3.95e-01 1.59e+00
go:0007492 endoderm development 3.68e-03 5.17e-02 4.32e-01 5.51e-01 1.74e+00
go:0048638 regulation of developmental growth 3.68e-03 5.17e-02 4.32e-01 3.96e-01 1.59e+00
go:1901699 cellular response to nitrogen compound 3.73e-03 5.20e-02 4.32e-01 3.31e-01 1.47e+00
go:0032153 cell division site 3.72e-03 5.20e-02 4.32e-01 5.06e-01 1.73e+00
go:0051783 regulation of nuclear division 3.77e-03 5.22e-02 4.32e-01 3.78e-01 1.55e+00
reactome:R-HSA-5610780 Degradation of GLI1 by the proteasome 3.77e-03 5.22e-02 4.32e-01 -4.14e-01 -1.66e+00
go:0005125 cytokine activity 3.88e-03 5.34e-02 4.32e-01 -5.13e-01 -1.82e+00
go:0051301 cell division 3.89e-03 5.34e-02 4.32e-01 3.07e-01 1.42e+00
go:0048471 perinuclear region of cytoplasm 3.92e-03 5.34e-02 4.07e-01 3.11e-01 1.42e+00
go:0051240 positive regulation of multicellular organismal process 3.92e-03 5.34e-02 4.07e-01 2.86e-01 1.36e+00
go:0006356 regulation of transcription by RNA polymerase I 3.95e-03 5.36e-02 4.07e-01 6.22e-01 1.76e+00
go:0030424 axon 4.03e-03 5.43e-02 4.07e-01 3.50e-01 1.50e+00
go:0002183 cytoplasmic translational initiation 4.04e-03 5.43e-02 4.07e-01 5.49e-01 1.73e+00
reactome:R-HSA-373755 Semaphorin interactions 4.08e-03 5.46e-02 4.07e-01 5.78e-01 1.78e+00
go:0030545 receptor regulator activity 4.10e-03 5.47e-02 4.07e-01 -3.69e-01 -1.60e+00
go:0000790 chromatin 4.14e-03 5.47e-02 4.07e-01 3.51e-01 1.50e+00
go:0097529 myeloid leukocyte migration 4.12e-03 5.47e-02 4.07e-01 -4.39e-01 -1.68e+00
go:0006936 muscle contraction 4.13e-03 5.47e-02 4.07e-01 4.11e-01 1.62e+00
go:0009055 electron transfer activity 4.18e-03 5.50e-02 4.07e-01 -3.69e-01 -1.60e+00
go:1905268 negative regulation of chromatin organization 4.22e-03 5.53e-02 4.07e-01 5.47e-01 1.73e+00
reactome:R-HSA-5689901 Metalloprotease DUBs 4.42e-03 5.77e-02 4.07e-01 -5.81e-01 -1.84e+00
go:0015931 nucleobase-containing compound transport 4.50e-03 5.81e-02 4.07e-01 3.56e-01 1.52e+00
go:0005126 cytokine receptor binding 4.50e-03 5.81e-02 4.07e-01 -3.92e-01 -1.63e+00
reactome:R-HSA-9020702 Interleukin-1 signaling 4.50e-03 5.81e-02 4.07e-01 -3.91e-01 -1.63e+00
go:0007167 enzyme linked receptor protein signaling pathway 4.56e-03 5.84e-02 4.07e-01 2.96e-01 1.37e+00
go:0000228 nuclear chromosome 4.61e-03 5.84e-02 4.07e-01 3.13e-01 1.42e+00
go:0043484 regulation of RNA splicing 4.58e-03 5.84e-02 4.07e-01 4.00e-01 1.60e+00
go:0060341 regulation of cellular localization 4.56e-03 5.84e-02 4.07e-01 2.96e-01 1.38e+00
go:0000781 chromosome, telomeric region 4.61e-03 5.84e-02 4.07e-01 4.03e-01 1.60e+00
reactome:R-HSA-5651801 PCNA-Dependent Long Patch Base Excision Repair 4.71e-03 5.85e-02 4.07e-01 -6.05e-01 -1.86e+00
go:0017171 serine hydrolase activity 4.70e-03 5.85e-02 4.07e-01 -5.15e-01 -1.77e+00
go:1902903 regulation of supramolecular fiber organization 4.71e-03 5.85e-02 4.07e-01 3.54e-01 1.49e+00
go:0050806 positive regulation of synaptic transmission 4.70e-03 5.85e-02 4.07e-01 5.43e-01 1.72e+00
go:0010639 negative regulation of organelle organization 5.01e-03 6.16e-02 4.07e-01 3.43e-01 1.50e+00
go:0003678 DNA helicase activity 5.00e-03 6.16e-02 4.07e-01 5.42e-01 1.71e+00
reactome:R-HSA-73933 Resolution of Abasic Sites (AP sites) 4.99e-03 6.16e-02 4.07e-01 -5.20e-01 -1.77e+00
go:0016758 transferase activity, transferring hexosyl groups 5.05e-03 6.18e-02 4.07e-01 -3.99e-01 -1.65e+00
go:0070987 error-free translesion synthesis 5.13e-03 6.25e-02 4.07e-01 -6.01e-01 -1.85e+00
reactome:R-HSA-110320 Translesion Synthesis by POLH 5.13e-03 6.25e-02 4.07e-01 -6.01e-01 -1.85e+00
msig:M16853 KEGG_DNA_REPLICATION 5.20e-03 6.31e-02 4.07e-01 -5.11e-01 -1.75e+00
go:0050808 synapse organization 5.22e-03 6.31e-02 4.07e-01 3.72e-01 1.52e+00
go:0002520 immune system development 5.30e-03 6.35e-02 4.07e-01 3.01e-01 1.39e+00
go:0009790 embryo development 5.30e-03 6.35e-02 4.07e-01 3.03e-01 1.39e+00
reactome:R-HSA-174417 Telomere C-strand (Lagging Strand) Synthesis 5.35e-03 6.38e-02 4.07e-01 -5.98e-01 -1.84e+00
reactome:R-HSA-381340 Transcriptional regulation of white adipocyte differentiation 5.44e-03 6.46e-02 4.07e-01 -4.50e-01 -1.67e+00
go:0005198 structural molecule activity 5.48e-03 6.47e-02 4.07e-01 3.01e-01 1.39e+00
go:0120111 neuron projection cytoplasm 5.47e-03 6.47e-02 4.07e-01 5.01e-01 1.68e+00
go:0071824 protein-DNA complex subunit organization 5.56e-03 6.55e-02 4.07e-01 3.57e-01 1.50e+00
go:0005839 proteasome core complex 5.64e-03 6.61e-02 4.07e-01 -6.12e-01 -1.82e+00
go:0031056 regulation of histone modification 5.65e-03 6.61e-02 4.07e-01 4.16e-01 1.62e+00
reactome:R-HSA-110373 Resolution of AP sites via the multiple-nucleotide patch replacement pathway 5.67e-03 6.61e-02 4.07e-01 -5.72e-01 -1.84e+00
go:0090199 regulation of release of cytochrome c from mitochondria 5.76e-03 6.67e-02 4.07e-01 -5.40e-01 -1.77e+00
go:0031098 stress-activated protein kinase signaling cascade 5.75e-03 6.67e-02 4.07e-01 3.87e-01 1.56e+00
go:0030031 cell projection assembly 5.80e-03 6.70e-02 4.07e-01 3.21e-01 1.43e+00
reactome:R-HSA-9012999 RHO GTPase cycle 5.89e-03 6.75e-02 4.07e-01 5.02e-01 1.65e+00
go:0006360 transcription by RNA polymerase I 5.89e-03 6.75e-02 4.07e-01 4.92e-01 1.66e+00
go:0032784 regulation of DNA-templated transcription, elongation 6.00e-03 6.86e-02 4.07e-01 5.38e-01 1.72e+00
go:0050877 nervous system process 6.04e-03 6.88e-02 4.07e-01 3.46e-01 1.50e+00
go:0005635 nuclear envelope 6.08e-03 6.91e-02 4.07e-01 3.20e-01 1.42e+00
go:0042734 presynaptic membrane 6.15e-03 6.96e-02 4.07e-01 5.87e-01 1.78e+00
go:0098632 cell-cell adhesion mediator activity 6.28e-03 7.09e-02 4.07e-01 6.09e-01 1.72e+00
go:1990904 ribonucleoprotein complex 6.44e-03 7.16e-02 4.07e-01 2.66e-01 1.29e+00
go:0006354 DNA-templated transcription, elongation 6.40e-03 7.16e-02 4.07e-01 3.99e-01 1.56e+00
go:0007417 central nervous system development 6.44e-03 7.16e-02 4.07e-01 3.10e-01 1.41e+00
go:0014855 striated muscle cell proliferation 6.39e-03 7.16e-02 4.07e-01 6.03e-01 1.73e+00
go:0043087 regulation of GTPase activity 6.37e-03 7.16e-02 4.07e-01 3.57e-01 1.50e+00
go:0051028 mRNA transport 6.51e-03 7.17e-02 4.07e-01 3.66e-01 1.50e+00
reactome:R-HSA-5685942 HDR through Homologous Recombination (HRR) 6.62e-03 7.27e-02 4.07e-01 -4.42e-01 -1.64e+00
go:0003729 mRNA binding 6.77e-03 7.40e-02 4.07e-01 3.50e-01 1.49e+00
go:2001251 negative regulation of chromosome organization 6.79e-03 7.40e-02 4.07e-01 4.07e-01 1.59e+00
go:0070252 actin-mediated cell contraction 6.92e-03 7.52e-02 4.07e-01 5.33e-01 1.70e+00
reactome:R-HSA-5619084 ABC transporter disorders 7.02e-03 7.56e-02 4.07e-01 -4.03e-01 -1.66e+00
go:0032465 regulation of cytokinesis 7.01e-03 7.56e-02 4.07e-01 4.77e-01 1.65e+00
reactome:R-HSA-9604323 Negative regulation of NOTCH4 signaling 7.04e-03 7.56e-02 4.07e-01 -4.00e-01 -1.61e+00
go:0030261 chromosome condensation 7.11e-03 7.57e-02 4.07e-01 5.72e-01 1.74e+00
go:0008022 protein C-terminus binding 7.12e-03 7.57e-02 4.07e-01 3.91e-01 1.56e+00
go:0032102 negative regulation of response to external stimulus 7.08e-03 7.57e-02 4.07e-01 -3.42e-01 -1.51e+00
go:0048285 organelle fission 7.22e-03 7.64e-02 4.07e-01 3.21e-01 1.42e+00
go:0016491 oxidoreductase activity 7.24e-03 7.64e-02 4.07e-01 -2.45e-01 -1.30e+00
go:0043967 histone H4 acetylation 7.29e-03 7.66e-02 4.07e-01 5.08e-01 1.65e+00
go:0044839 cell cycle G2/M phase transition 7.33e-03 7.69e-02 4.07e-01 3.37e-01 1.47e+00
go:0046330 positive regulation of JNK cascade 7.37e-03 7.71e-02 4.07e-01 5.30e-01 1.69e+00
go:0001706 endoderm formation 7.42e-03 7.72e-02 4.07e-01 5.99e-01 1.72e+00
go:0022412 cellular process involved in reproduction in multicellular organism 7.43e-03 7.72e-02 4.07e-01 3.96e-01 1.55e+00
go:0044770 cell cycle phase transition 7.52e-03 7.79e-02 4.07e-01 2.91e-01 1.35e+00
reactome:R-HSA-194315 Signaling by Rho GTPases 7.53e-03 7.79e-02 4.07e-01 3.19e-01 1.41e+00
go:0048010 vascular endothelial growth factor receptor signaling pathway 7.64e-03 7.87e-02 4.07e-01 4.95e-01 1.65e+00
go:0031490 chromatin DNA binding 7.69e-03 7.88e-02 4.07e-01 4.52e-01 1.62e+00
reactome:R-HSA-5653656 Vesicle-mediated transport 7.69e-03 7.88e-02 4.07e-01 2.96e-01 1.37e+00
go:0031330 negative regulation of cellular catabolic process 7.78e-03 7.93e-02 4.07e-01 3.67e-01 1.51e+00
reactome:R-HSA-9013694 Signaling by NOTCH4 7.79e-03 7.93e-02 4.07e-01 -3.77e-01 -1.59e+00
reactome:R-HSA-4608870 Asymmetric localization of PCP proteins 7.82e-03 7.95e-02 3.81e-01 -4.02e-01 -1.58e+00
go:0060589 nucleoside-triphosphatase regulator activity 7.91e-03 7.99e-02 3.81e-01 3.63e-01 1.49e+00
go:0032201 telomere maintenance via semi-conservative replication 7.96e-03 7.99e-02 3.81e-01 -5.65e-01 -1.77e+00
go:0007018 microtubule-based movement 7.95e-03 7.99e-02 3.81e-01 3.65e-01 1.49e+00
go:0048738 cardiac muscle tissue development 8.02e-03 8.01e-02 3.81e-01 4.43e-01 1.63e+00
go:0016298 lipase activity 8.01e-03 8.01e-02 3.81e-01 -5.97e-01 -1.77e+00
go:0044068 modulation by symbiont of host cellular process 8.12e-03 8.02e-02 3.81e-01 6.12e-01 1.66e+00
go:0042180 cellular ketone metabolic process 8.08e-03 8.02e-02 3.81e-01 -3.38e-01 -1.51e+00
go:0032870 cellular response to hormone stimulus 8.11e-03 8.02e-02 3.81e-01 3.14e-01 1.41e+00
go:0051345 positive regulation of hydrolase activity 8.10e-03 8.02e-02 3.81e-01 3.07e-01 1.38e+00
reactome:R-HSA-5678895 Defective CFTR causes cystic fibrosis 8.19e-03 8.06e-02 3.81e-01 -3.82e-01 -1.55e+00
go:0045309 protein phosphorylated amino acid binding 8.21e-03 8.07e-02 3.81e-01 5.99e-01 1.69e+00
go:0007052 mitotic spindle organization 8.30e-03 8.13e-02 3.81e-01 4.21e-01 1.60e+00
go:0030427 site of polarized growth 8.35e-03 8.16e-02 3.81e-01 4.34e-01 1.59e+00
go:0006323 DNA packaging 8.43e-03 8.22e-02 3.81e-01 3.89e-01 1.55e+00
go:0098978 glutamatergic synapse 8.48e-03 8.24e-02 3.81e-01 3.78e-01 1.52e+00
go:0035591 signaling adaptor activity 8.58e-03 8.31e-02 3.81e-01 5.73e-01 1.73e+00
go:0051248 negative regulation of protein metabolic process 8.60e-03 8.31e-02 3.81e-01 2.83e-01 1.33e+00
go:0032392 DNA geometric change 8.63e-03 8.32e-02 3.81e-01 4.25e-01 1.59e+00
go:0010720 positive regulation of cell development 8.71e-03 8.32e-02 3.81e-01 3.39e-01 1.46e+00
go:0043297 apical junction assembly 8.79e-03 8.32e-02 3.81e-01 5.62e-01 1.75e+00
reactome:R-HSA-4641258 Degradation of DVL 8.79e-03 8.32e-02 3.81e-01 -3.98e-01 -1.57e+00
reactome:R-HSA-69541 Stabilization of p53 8.75e-03 8.32e-02 3.81e-01 -3.92e-01 -1.57e+00
go:0003774 motor activity 8.75e-03 8.32e-02 3.81e-01 4.59e-01 1.62e+00
go:0005871 kinesin complex 8.77e-03 8.32e-02 3.81e-01 5.92e-01 1.73e+00
go:0070849 response to epidermal growth factor 8.67e-03 8.32e-02 3.81e-01 5.63e-01 1.75e+00
go:0045935 positive regulation of nucleobase-containing compound metabolic process 8.86e-03 8.34e-02 3.81e-01 3.56e-01 1.49e+00
reactome:R-HSA-73929 Base-Excision Repair, AP Site Formation 8.86e-03 8.34e-02 3.81e-01 -5.93e-01 -1.76e+00
go:0007264 small GTPase mediated signal transduction 9.01e-03 8.45e-02 3.81e-01 3.24e-01 1.42e+00
reactome:R-HSA-69186 Lagging Strand Synthesis 9.05e-03 8.47e-02 3.81e-01 -5.92e-01 -1.76e+00
go:0016655 oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor 9.09e-03 8.49e-02 3.81e-01 -3.95e-01 -1.62e+00
go:0040014 regulation of multicellular organism growth 9.13e-03 8.50e-02 3.81e-01 5.85e-01 1.75e+00
go:0034330 cell junction organization 9.22e-03 8.56e-02 3.81e-01 3.60e-01 1.49e+00
go:0001508 action potential 9.31e-03 8.61e-02 3.81e-01 5.45e-01 1.72e+00
go:0019953 sexual reproduction 9.32e-03 8.61e-02 3.81e-01 3.22e-01 1.43e+00
reactome:R-HSA-446652 Interleukin-1 family signaling 9.37e-03 8.63e-02 3.81e-01 -3.62e-01 -1.55e+00
go:1904888 cranial skeletal system development 9.41e-03 8.65e-02 3.81e-01 5.90e-01 1.73e+00
go:0032504 multicellular organism reproduction 9.49e-03 8.70e-02 3.81e-01 3.24e-01 1.44e+00
go:0060996 dendritic spine development 9.55e-03 8.71e-02 3.81e-01 4.84e-01 1.59e+00
go:0071242 cellular response to ammonium ion 9.55e-03 8.71e-02 3.81e-01 5.94e-01 1.68e+00
reactome:R-HSA-5632684 Hedgehog 'on' state 9.70e-03 8.83e-02 3.81e-01 -3.93e-01 -1.62e+00
go:0032154 cleavage furrow 9.74e-03 8.83e-02 3.81e-01 5.04e-01 1.66e+00
go:0045596 negative regulation of cell differentiation 9.75e-03 8.83e-02 3.81e-01 3.20e-01 1.41e+00
go:0060326 cell chemotaxis 9.88e-03 8.92e-02 3.81e-01 -3.70e-01 -1.57e+00
go:0098609 cell-cell adhesion 9.99e-03 8.99e-02 3.81e-01 3.22e-01 1.42e+00
go:0051168 nuclear export 1.01e-02 9.05e-02 3.81e-01 3.37e-01 1.43e+00
go:0000070 mitotic sister chromatid segregation 1.01e-02 9.05e-02 3.81e-01 3.66e-01 1.49e+00
go:0045740 positive regulation of DNA replication 1.04e-02 9.11e-02 3.81e-01 5.91e-01 1.67e+00
go:0007276 gamete generation 1.04e-02 9.11e-02 3.81e-01 3.27e-01 1.42e+00
go:0036475 neuron death in response to oxidative stress 1.04e-02 9.11e-02 3.81e-01 6.06e-01 1.64e+00
go:0009792 embryo development ending in birth or egg hatching 1.04e-02 9.11e-02 3.81e-01 3.16e-01 1.40e+00
reactome:R-HSA-8852276 The role of GTSE1 in G2/M progression after G2 checkpoint 1.03e-02 9.11e-02 3.81e-01 -3.70e-01 -1.57e+00
go:0060090 molecular adaptor activity 1.03e-02 9.11e-02 3.81e-01 3.96e-01 1.53e+00
go:0005874 microtubule 1.05e-02 9.17e-02 3.81e-01 3.30e-01 1.44e+00
go:0051653 spindle localization 1.05e-02 9.18e-02 3.81e-01 5.47e-01 1.66e+00
go:0000819 sister chromatid segregation 1.06e-02 9.23e-02 3.81e-01 3.64e-01 1.52e+00
go:1902369 negative regulation of RNA catabolic process 1.07e-02 9.24e-02 3.81e-01 5.36e-01 1.69e+00
go:0002682 regulation of immune system process 1.08e-02 9.28e-02 3.81e-01 2.79e-01 1.32e+00
go:0007281 germ cell development 1.07e-02 9.28e-02 3.81e-01 4.20e-01 1.56e+00
reactome:R-HSA-6802952 Signaling by BRAF and RAF1 fusions 1.08e-02 9.28e-02 3.81e-01 5.18e-01 1.66e+00
go:0010257 NADH dehydrogenase complex assembly 1.08e-02 9.28e-02 3.81e-01 -3.85e-01 -1.60e+00
go:0060322 head development 1.10e-02 9.44e-02 3.81e-01 3.06e-01 1.37e+00
go:0008023 transcription elongation factor complex 1.11e-02 9.53e-02 3.81e-01 4.77e-01 1.57e+00
msig:M5898 HALLMARK_DNA_REPAIR 1.13e-02 9.62e-02 3.81e-01 -3.17e-01 -1.46e+00
go:0051015 actin filament binding 1.14e-02 9.69e-02 3.81e-01 4.11e-01 1.57e+00
go:0016358 dendrite development 1.14e-02 9.71e-02 3.81e-01 4.18e-01 1.58e+00
go:0090169 regulation of spindle assembly 1.16e-02 9.82e-02 3.81e-01 5.83e-01 1.70e+00
go:0000003 reproduction 1.18e-02 9.97e-02 3.81e-01 2.80e-01 1.31e+00
go:0043405 regulation of MAP kinase activity 1.19e-02 9.97e-02 3.81e-01 3.58e-01 1.47e+00

Literature Mining

INDRA was used to automatically assemble known mechanisms related to UCHL3 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach
UCHL3 deubiquitinates RAD51. 6 / 6
| 5

UCHL3 deubiquitinates RAD51 thereby promoting the recruitment of RAD51 to DNA damage sites and augmenting DNA repair.

RAD51 deubiquitination by UCHL3 was observed both in vitro and in cellulo and shown to be critical for BRCA2-RAD51 interaction, RAD51 recruitment to DSB sites, foci formation, as well as RAD51 mediated D-loop formation [XREF_BIBR].

After DNA damages, UCHL3 is activated via phosphorylation by ATM and then deubiquitinates RAD51 promoting RAD51-BRCA2 interaction and proper HR repair [150].

found that UCHL3 deubiquitinates RAD51 and subsequently facilitates RAD51-BRCA2 interaction, which is critical for homologous recombination (HR) and contributes to therapeutic resistance in breast cancer.

UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.

UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.
UCHL3 deubiquitinates COPS5. 4 / 4
| 4

Given that UCHL3 interacts with COPS5 in IFN signaling and UCHL3 is a deubiquitinase, we question whether UCHL3 promotes COPS5 deubiquitination.

To address this question, we firstly performed an in vitro deubiquitination assay, which clearly demonstrated that UCHL3 can deubiquitinate COPS5 in vitro.

These results imply that UCHL3 physically interacts with COPS5 and deubiquitinates COPS5.Given that UCHL3 can deubiquitinate COPS5, we speculate that UCHL3 could affect cellular levels of COPS5.

Furthermore, we demonstrate that UCHL3 as a deubiquitinase can deubiquitinate COPS5, thereby upregulating COPS5 levels and protein stability (Figs. 4 and 5).
UCHL3 deubiquitinates FOXM1. 2 / 2
| 2

Furthermore, knockdown of UCHL3 increased FOXM1 ubiquitination, which enhanced FOXM1 turnover and promoted pancreatic cancer cells ' sensitivity to gemcitabine.

Deubiquitination of FOXM1 by UCHL3 was also shown to promote pancreatic cancer progression and gemcitabine resistance.
UCHL3 leads to the deubiquitination of TRAF2. 2 / 2
| 2

UCHL3 was found to activate NF-kappaB signalling by deubiquitinating and stabilizing TRAF2, leading to tumourigenesis.

The elevated UCHL3 facilitates carcinogenesis and enhances inflammation by deubiquitinating and stabilizing TNF Receptor Associated Factor 2 (TRAF2).
UCHL3 leads to the deubiquitination of TDP1. 1 / 1
| 1

In contrast, UCHL3 is downregulated in spinocerebellar ataxia with axonal neuropathy (SCAN1), causing elevated levels of TDP1 ubiquitylation and faster turnover rate.
UCHL3 deubiquitinates RAD51B. 1 / 1

Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2.
UCHL3 deubiquitinates PPARG. 1 / 1
| 1

In addition, recombinant UCHL3 failed to deubiquitinate PPARgamma in vitro (XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY), indicating that UCHL3 modulates PPARgamma activity by an indirect mechanism, either through its ubiquitin hydrolase or its deneddylase activity.
UCHL3 deubiquitinates MCL1. 1 / 1
| 1

Cdu1, but not the control enzyme UCH-L3 strongly deubiquitinated Mcl-1 (XREF_FIG).
UCHL3 deubiquitinates STUB1. 1 / 1
| 1

No other tested DUB behaved in a similar manner : USP5 deubiquitinated Ub-CHIP in an unregulated manner, while UCHL-1 and UCHL-3 did not deubiquitinate Ub-CHIP under any conditions (XREF_FIG).
UCHL3 deubiquitinates SMAD1. 1 / 1

Ubiquitin C-terminal hydrolase-L3 regulates Smad1 ubiquitination and osteoblast differentiation.
Modified UCHL3 leads to the deubiquitination of TDP1. 1 / 1
| 1

Overexpression of UCHL3, but not a catalytically inactive mutant, suppresses TDP1 ubiquitylation and turnover rate.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

The induction of EMT by UCH-L3 knockdown results in an increase of cell migration and invasion.

UCH-L3 was found to be downregulated in the highly metastatic prostate cell lines, and knockdown of UCH-L3 induced EMT process.

Contrarily, overexpression of UCH-L3 in the highly metastatic prostate cell line PC3 reverses EMT depending on the deubiquitinating activity of UCH-L3.

The reverse of the EMT event caused by UCH-L3 overexpression in PC3 coincided with a decrease of cell migration and invasion.UCH-L3 and UCH-L1 are very close relatives with high amino acid identity an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

Yet, to the contrary, overexpression of UCH-L3 in highly metastatic prostate cancer cell line PC3 reverses EMT but the active site mutant UCH-L3 did not.

As shown in Fig. 2 B, knockdown of UCH-L3 induces the molecular alterations of EMT.

By contrast , UCHL3 is reduced in metastatic prostate cancer cell lines , and knockdown of UCHL3 promotes epithelial-to-mesenchymal transition ( EMT ) , contributing to cancer cell invasion and metastasis ( 102 ) .

These results indicate that UCH-L3 inhibits EMT by repression of EMT promoting genes such as Snail , Slug , Twist , and MMPs in normal prostate cell lines.

These results indicate that UCH-L3 inhibits EMT by repression of EMT promoting genes such as Snail, Slug, Twist, and MMPs in normal prostate cell lines.In our previous report, we found that UCH-L1 exp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

We found that knockdown of UCH-L3 induced EMT process.

Knockdown of UCH-L3 in the normal prostate cell line RWPE1 induces morphological and molecular events of EMT.

We have already shown that UCH-L1, a close relative of UCH-L3, induces EMT and promotes metastasis in prostate cancer cells [11].
UCHL3 increases the amount of epithelial to mesenchymal transition.
| 1
Modified UCHL3 increases the amount of epithelial to mesenchymal transition. 1 / 1
| 1

The alterations of the EMT marker expression induced by UCH-L3 overexpression in PC3 stable cells coincided with the change of migratory and invasive properties.
Ubiquitin affects UCHL3
| 1 4 6
Ubiquitin inhibits UCHL3.
| 1 4 5
| 1 4 5

As an additional control experiment, we measured a K i of 0.27 mM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

As an additional control experiment, we measured a K i of 0.27 muM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

Using our Ub tools to profile UCHL3's activity, we generate a quantitative kinetic model of the inhibitory mechanism and we find that K27 Ub 2 can inhibit UCHL3 covalently, by binding to its catalytic cysteine, and allosterically, by locking its catalytic loop tightly in place.

As an additional control experiment, we measured a K i of 0.27 mM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

As an additional control experiment, we measured a Ki of 0.27 μM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

As an additional control experiment, we measured a K of 0.27 μM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

As an additional control experiment, we measured a Ki of 0.27 μM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC.

The present data demonstrated that ubiquitin aldehyde can inhibit the activity of UCHL3.

(2) The kinetics of inhibition of UCH-L3 by ubiquitin C-terminal aldehyde (Ub-H) were determined and reveal a Ki that is less than 10 (-14) M. Several mechanisms are considered to account for the extreme inhibition.

As an additional control experiment , we measured a K i of 0.27 mM for the inhibition of UCH-L3 by ubiquitin with the substrate ubiquitin-AMC .
Ubiquitin increases the amount of UCHL3.
| 1
Ubiquitin increases the amount of UCHL3. 1 / 1
| 1

Therefore, ubiquitin aldehyde may modulate the protein expression and function of UCHL3.
8 |
Valproic acid increases the amount of UCHL3. 8 / 8
8 |

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UCHL3 affects COPS5
| 8
UCHL3 increases the amount of COPS5.
| 5
UCHL3 bound to COPS5 increases the amount of COPS5. 2 / 2
| 2

We demonstrate that UCHL3 physically interacts with COPS5, and increases COPS5 levels and protein stability by deubiquitinating COPS5.

Next, we find that UCHL3 physically interacts with COPS5, and upregulates COPS5 levels and protein stability by deubiquitinating COPS5.
UCHL3 increases the amount of COPS5. 2 / 2
| 2

Furthermore, we demonstrate that UCHL3 as a deubiquitinase can deubiquitinate COPS5, thereby upregulating COPS5 levels and protein stability (Figs. 4 and 5).

In summary, our results demonstrate that UCHL3 upregulates the levels of SCF beta-TrCP substrates.We have demonstrated that UCHL3 positively regulated COPS5 levels and IFNAR1 levels.
Modified UCHL3 increases the amount of COPS5. 1 / 1
| 1

Meanwhile, endogenous COPS5 levels were also gradually upregulated by overexpression of increased amounts of UCHL3.
UCHL3 decreases the amount of COPS5.
| 2
UCHL3 decreases the amount of COPS5. 2 / 2
| 2

Since COPS5 have been demonstrated to downregulate Cullin1 neddylation and activity, we speculate that UCHL3 could downregulate the activity of SCF beta and TrCP complex by upregulating cellular COPS5[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

We found that UCHL3 knockdown noticeably upregulated ubiquitination levels of COPS5.
UCHL3 activates COPS5.
| 1
UCHL3 activates COPS5. 1 / 1
| 1

The result showed that FH-UCHL3 overexpression obviously blocked protein degradation of COPS5, suggesting that UCHL3 enhances COPS5 protein stability.
UCHL3 affects CUL1
| 7
UCHL3 inhibits CUL1.
| 4
UCHL3 inhibits CUL1. 4 / 4
| 4

We reveal that UCHL3 can inhibit Cullin1 neddylation in cells dependently on COPS5.

We found that overexpression of increased amounts of UCHL3 gradually inhibited endogenous Cullin1 neddylation, indicating that cellular Cullin1 neddylation are regulated by UCHL3 levels.

Our results showed that UCHL3 overexpression inhibits Cullin1 neddylation.

We find that in cells UCHL3 can decrease neddylation of Cullin1.
UCHL3 activates CUL1.
| 2
UCHL3 activates CUL1. 2 / 2
| 2

Subsequently, UCHL3 mediated upregulation of COPS5 promotes Cullin1 deneddylation.

However, we found that knockout of COPS5 abolished the effect of UCHL3 on Cullin1 deneddylation, indicating that COPS5 is required for UCHL3 mediated deneddylation of Cullin1 in cells.
UCHL3 decreases the amount of CUL1.
| 1
Modified UCHL3 decreases the amount of CUL1. 1 / 1
| 1

Our data showed that overexpression of UCHL3 in COPS5-wild type (WT) cells robustly decreased Cullin1 neddylation levels, consistent with our previous observation.

UCH-L3 knockdown significantly inhibited the proliferation of NSCLC cells, whereas UCH-L3 overexpression had the opposite effect.

UCHL3 promotes proliferation of colorectal cancer cells by regulating SOX12 via AKT and mTOR signaling pathway.

UCH-L3 promotes non small cell lung cancer proliferation via accelerating cell cycle and inhibiting cell apoptosis.

Moreover, UCH-L3 promoted NSCLC cells proliferation via accelerating cell cycle and inhibiting cell apoptosis.

Taken together, the results of the present study suggest that UCHL3 knockdown decreases melanoma cell proliferation by increasing cell autophagy through regulating NEDD8 expression and autophagosome numbers.

Genetic ablation of UCHL3 was found to markedly block ovarian cancer cell proliferation, viability and migration both in vitro and in vivo.

Even though the function of UCH-L3 in neurons has not been elucidated to the extent of our knowledge, it may be plausible that there can be reciprocal or differential functions of UCH-L3 to the UCH-L1[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

These results suggest that Uch-L3 enhances osteoblast differentiation through the stabilization of Smad1 signaling.

Consequently, it was suggested that UCHL3 stabilizes Smad1 signaling, which may explain the enhanced osteoblast differentiation caused by UCHL3 overexpression.
Modified UCHL3 activates cell differentiation. 1 / 1
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Moreover, ectopic expression of wild-type UCH-L3 restored the phosphorylation of insulin and IGF-I receptor and adipocyte differentiation in Uchl3 (-/-) MEFs.
UCHL3 affects TDP1
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UCHL3 decreases the amount of TDP1.
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UCHL3 decreases the amount of TDP1. 3 / 3
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Depletion of UCHL3 was sufficient to reduce TDP1 expression in rhabdomyosarcoma cells to levels comparable to control cells (XREF_FIG D, top) and led to hypersensitivity to the TOP1 poison CPT (XREF_FIG D, bottom).

UCHL3 decreases the ubiquitination level of TDP1 leading to the inhibition of TDP1 degradation.

Depletion of UCHL3 in rhabdomyosarcoma cells reduced TDP1 levels and sensitized cells to TOP1 poisons.
UCHL3 increases the amount of TDP1.
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Modified UCHL3 increases the amount of TDP1. 1 / 1
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TDP1 overexpression in the topoisomerase therapy resistant rhabdomyosarcoma is driven by UCHL3 overexpression.
UCHL3 activates TDP1.
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UCHL3 activates TDP1. 1 / 1
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Depletion of UCHL3 in rhabdomyosarcoma cells markedly accelerated TDP1 turnover, as measured by CHX chase experiments (XREF_FIG B).
UCHL3 affects KITLG
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UCHL3 activates KITLG. 4 / 4
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We further demonstrate that UCHL3 upregulates the levels of SCF beta-TrCP substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity.

Furthermore, we reveal that UCHL3 increases levels of SCF beta-TrCP substrates and enhances IFN-I mediated signaling and antiviral activity.

Thus, our findings identify a novel in vivo substrate of UCHL3, and reveal a novel deneddylation regulation by UCHL3.It is interesting that UCHL3 controls the activity of cellular SCF beta and TrCP co[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

Moreover, we find that UCHL3 upregulates levels of SCF beta-TrCP substrates including IFN-I receptor IFNAR1, thereby enhancing IFN-I mediated signaling and antiviral activity.
UCHL3 affects UCHL1
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UCHL3 inhibits UCHL1.
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UCHL3 inhibits UCHL1. 2 / 2
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The screening of over 40 000 compounds against the closely related ubiquitin Cterminal hydrolase L1 (UCH-L1) and L3 (UCH-L3) enzymes allowed the development of a UCHL1-specific inhibitor based on an isatin O-acyl oxime scaffold [105] .

We found that UCH-L1 is highly induced by UCH-L3 knockdown in RWPE1.
UCHL3 decreases the amount of UCHL1.
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UCHL3 decreases the amount of UCHL1. 1 / 1
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Interestingly, we found that knockdown of UCH-L3 induces the expression of UCH-L1 which is repressed by epigenetic modification in RWPE1.
UCHL3 activates UCHL1.
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UCHL3 activates UCHL1. 1 / 1
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UCHL1 and UCHL3 are 73% similar but display different patterns of tissue specific gene expression : an upstream neuron-restrictive silencing element (NRSE) drives neuron specific expression in the former and renders it a critical player in neuronal homeostasis (UCHL1 deficiency in neurodegeneration is not physiologically rescued by UCHL3).
UCHL3 affects IFNAR1
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UCHL3 increases the amount of IFNAR1.
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UCHL3 increases the amount of IFNAR1. 2 / 2
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These findings suggest that UCHL3 could positively regulate IFNAR1 levels via COPS5 mediated deneddylation of Cullin1, which is consistent with our previous findings that UCHL3 positively regulates IF[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

In summary, our results demonstrate that UCHL3 upregulates the levels of SCF beta-TrCP substrates.We have demonstrated that UCHL3 positively regulated COPS5 levels and IFNAR1 levels.
Modified UCHL3 increases the amount of IFNAR1. 1 / 1
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The result showed that UCHL3 overexpression gradually increased IFNAR1 levels.
UCHL3 activates IFNAR1.
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UCHL3 activates IFNAR1. 1 / 1
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This finding suggests that UCHL3 could target either TYK2 itself or IFN-I receptors (IFNAR1 and IFNAR2), which are the direct proteins upstream of TYK2 as well as the first signaling proteins in IFN-I[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Trichostatin A increases the amount of UCHL3. 3 / 3
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Cobalt dichloride decreases the amount of UCHL3. 3 / 3
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UBD affects UCHL3
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