BRCC3 Data Analysis

HGNC Gene Name
BRCA1/BRCA2-containing complex subunit 3
HGNC Gene Symbol
BRCC3
Identifiers
hgnc:24185 NCBIGene:79184 uniprot:P46736
Orthologs
mgi:2389572 rgd:1588543
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for BRCC3
Number of Papers
92 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
SPANXN5 SPANX family member N5 0.222
BABAM1 BRISC and BRCA1 A complex member 1 0.209 BioGRID IntAct NURSA INDRA (2) Reactome (16) 0.46 2.44 3.49e-19
ABL1 ABL proto-oncogene 1, non-receptor tyrosine kinase 0.206 Reactome (7) 0.08 0.35 2.26e-01
AFF2 AF4/FMR2 family member 2 0.204
ABRAXAS2 abraxas 2, BRISC complex subunit 0.199 BioGRID IntAct NURSA INDRA (3) Reactome (4)
RHOXF2 Rhox homeobox family member 2 0.196
C12orf73 chromosome 12 open reading frame 73 0.194 -0.04 -0.30 6.24e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with BRCC3using 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:0070552 BRISC complex Cellular Component 5.55e-07 2.20e-04 8.54e-05
GO:0070536 protein K63-linked deubiquitination Biological Process 2.92e-05 1.16e-02 2.25e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out BRCC3 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
BRCC3 BRCA1/BRCA2-containing complex subunit 3 -1.16e+00 1.22e-07 2.70e-03

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to BRCC3 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
BRCC3 deubiquitinates NLRP3. 10 / 27
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Altogether, these results demonstrate that BRCC3 mediates the deubiquitination of the LRR domain of NLRP3, an important regulatory mechanism in the activation of NLRP3 inflammasome by its cognate stim[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Lys-63-specific deubiquitinase BRCC36 (BRCC3), a JAMM domain containing Zn 2+ metalloprotease, promotes NLRP3 deubiquitination during priming and regulates NLRP3 activation [26].

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Viral RNA (vRNA) molecule-induced NLRP3 inflammasome activation also comes about by post-translational priming, but involving the RIP1/caspase 8/RIP3 signaling pathway (29, 45), which may ultimately result in the deubiquitination of NLRP3 protein by BRCC3 (46, 47).

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The K-63-specific deubiquitinating enzyme BRCC3 mediates the deubiquitylation of NLRP3, which has recently been shown to occur in response to pattern recognition receptor stimulation [XREF_BIBR].

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BRCC3 inhibition promotes NLRP3 ubiquitination and blocks inflammasome assembly but does not target NLRP3 for degradation.

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BRCC3, a JAMM domain containing Zn2+ metalloprotease, promotes NLRP3 deubiquitination during priming and regulates NLRP3 activation [XREF_BIBR].

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Moreover, BRCC3 [18], STING [19] and ABRO1 [20] can be activated by NLRP3 agonists, such as ATP, to promote the deubiquitination and sensitivity of NLRP3.
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By screening a deubiquitinating enzyme (DUB) library, they recognized that BRCC3 (BRCA1, BRCA2, and containing complex subunit 3) deubiquitinates the LRR domain of NLRP3, which then proceeds NLRP3 activation 59.

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A previous study has demonstrated that BRCC3, a K63 specific deubiquitinase, enhances NLRP3 inflammasome activity by deubiquitinating NLRP3 35.

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NLRP3 deubiquitination is mediated by BRCC3, a member of JAMM domain containing Zn 2+ metalloprotease deubiquitinating enzyme family, therefore providing a novel therapeutic target for IL-1beta-associated inflammatory diseases.
BRCC3 deubiquitinates Interferon. 3 / 3
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In the BRCC36 isopeptidase complex, BRCC36 promotes interferon dependent responses by deubiquitinating and stabilizing the type I interferon receptor XREF_BIBR.

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Dr. Greenberg group from University of Pennsylvania showed that BRCC36 containing deubiquitinating complex BRISC which is also a sister protein complex of nuclear RAP80-BRCA1 complex, deubiquitinates type I interferon receptor (IFNAR1), resulting in its delayed lysosomal dependent degradation.

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The Abraxas complex (ARISC) functions in DNA repair and breast cancer suppression, while the BRCC36 isopeptidase complex (BRISC) promotes interferon dependent responses by deubiquitinating and stabilizing the type I interferon receptor, IFNAR1.
Modified BRCC3 leads to the deubiquitination of NLRP3. 1 / 1
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In addition, consistent with its role as a deubiquitination enzyme for NLRP3, BRCC3 expression significantly reduced the extent of NLRP3 covalent ubiquitination in 293T cells.
BRCC3 deubiquitinates H2AX. 1 / 1
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BRCA1/2-containing complex36 (BRCC36) is one of the DUBs which localizes at the site of DSBs as a part of the RAP80 complex and deubiquitinates RNF8-dependent γHA2X ubiquitination
BRCC3 deubiquitinates NUMA1. 1 / 1
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importantly, BRISC promotes the assembly of functional bipolar spindle by deubiquitinating the essential spindle assembly factor nuclear mitotic apparatus (NuMA).
BRCC3 deubiquitinates COPS5. 1 / 1
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To identify the DUB associated with NALP7, we over-expressed plasmids expressing several candidate DUBs including BRCC3, which deubiquitinates NALP3, COPS5, STAMBPL1, USP7 and the endosome associated DUBs, STAMBP and USP8.
BRCC3 deubiquitinates RNF8. 1 / 1
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This suggests that BRCC36 normally deubiquitylates the substrate of RNF8 and UBC13 at DSBs.
BRCC3 leads to the deubiquitination of NOD. 1 / 1
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BRCC3 have been shown to promote the inflammasome activation by deubiquitinating NOD like receptor containing pyrin domain 3 (NLRP3).
BRCC3 deubiquitinates UBE2N. 1 / 1
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This suggests that BRCC36 normally deubiquitylates the substrate of RNF8 and UBC13 at DSBs.
BRCC3 deubiquitinates H2AC17. 1 / 1
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Review
BRCC3 leads to the deubiquitination of SYK. 1 / 1
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Priming requires IRAK1 activation and proteasome dependent ERK activation (with downstream MEK1/2 activation), and it involves post-translational modifications including : (i) BRCC3 mediated NLRP3 deubiquitination, (ii) LUBAC mediated ASC ubiquitination, and (iii) SYK- and JNK dependent ASC phosphorylation.
BRCC3 deubiquitinates SGCG. 1 / 1
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Dr. Greenberg group from University of Pennsylvania showed that BRCC36 containing deubiquitinating complex BRISC which is also a sister protein complex of nuclear RAP80-BRCA1 complex, deubiquitinates type I interferon receptor (IFNAR1), resulting in its delayed lysosomal dependent degradation.
BRCC3 leads to the deubiquitination of NACHT on K64. 1 / 1
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Recently, Py and colleagues demonstrated that BRCC3, a JAMM domain containing zinc metalloprotease DUB, promotes NLRP3 inflammasome activation by deubiquitinating the mixed K64 and K48 ubiquitin chains on both the NACHT and LRR domains of NLRP3 [XREF_BIBR].
BRCC3 deubiquitinates Histone. 1 / 1
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There are many examples of HDACs being recruited to sites of DNA repair (as discussed above), and the BRCA-1A complex actually contains a DUB, Brcc36, that can deubiquitinate histones at least in vitro.
BRCC3 deubiquitinates IFNAR1. 1 / 1
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Dr. Greenberg group from University of Pennsylvania showed that BRCC36 containing deubiquitinating complex BRISC which is also a sister protein complex of nuclear RAP80-BRCA1 complex, deubiquitinates type I interferon receptor (IFNAR1), resulting in its delayed lysosomal dependent degradation.
BRCC3 leads to the deubiquitination of NACHT. 1 / 1
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Recently, Py and colleagues demonstrated that BRCC3, a JAMM domain containing zinc metalloprotease DUB, promotes NLRP3 inflammasome activation by deubiquitinating the mixed K64 and K48 ubiquitin chains on both the NACHT and LRR domains of NLRP3 [XREF_BIBR].
BRCC3 deubiquitinates STAMBPL1. 1 / 1
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To identify the DUB associated with NALP7, we over-expressed plasmids expressing several candidate DUBs including BRCC3, which deubiquitinates NALP3, COPS5, STAMBPL1, USP7 and the endosome associated DUBs, STAMBP and USP8.
BRCC3 deubiquitinates USP7. 1 / 1
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To identify the DUB associated with NALP7, we over-expressed plasmids expressing several candidate DUBs including BRCC3, which deubiquitinates NALP3, COPS5, STAMBPL1, USP7 and the endosome associated DUBs, STAMBP and USP8.
BRCC3 deubiquitinates JAK2. 1 / 1
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We show here that a LNK-associated lysine-63 (K63)-deubiquitinating enzyme complex, Brcc36 isopeptidase complex (BRISC), attenuates HSC expansion through control of JAK2 signaling.
BRCC3 leads to the deubiquitination of SMAD3. 1 / 1
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BRCC36 may inhibit the activation of the TGF-beta1 signaling pathway by regulating the ubiquitination of smad3.
BRCC3 deubiquitinates FANCG. 1 / 1
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?we demonstrated that K63Ub-modified FANCG was deubiquitinated by BRCC36 complex in vitro and in vivo
BRCC3 leads to the deubiquitination of NACHT on K48. 1 / 1
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Recently, Py and colleagues demonstrated that BRCC3, a JAMM domain containing zinc metalloprotease DUB, promotes NLRP3 inflammasome activation by deubiquitinating the mixed K64 and K48 ubiquitin chains on both the NACHT and LRR domains of NLRP3 [XREF_BIBR].
BRCC3 deubiquitinates TNKS. 1 / 1
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Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution
BRCC3 leads to the deubiquitination of lipopolysaccharide. 1 / 1
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Recently, BRCC3 in the cytosol has been reported to promote the inflammasome activation by deubiquitinating NLRP3 in LPS primed macrophages [XREF_BIBR].
BRCC3 leads to the deubiquitination of JNK. 1 / 1
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Priming requires IRAK1 activation and proteasome dependent ERK activation (with downstream MEK1/2 activation), and it involves post-translational modifications including : (i) BRCC3 mediated NLRP3 deubiquitination, (ii) LUBAC mediated ASC ubiquitination, and (iii) SYK- and JNK dependent ASC phosphorylation.
BRCC3 leads to the deubiquitination of PYCARD. 1 / 1
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Priming requires IRAK1 activation and proteasome dependent ERK activation (with downstream MEK1/2 activation), and it involves post-translational modifications including : (i) BRCC3 mediated NLRP3 deubiquitination, (ii) LUBAC mediated ASC ubiquitination, and (iii) SYK- and JNK dependent ASC phosphorylation.
BRCC3 deubiquitinates NLRP3 at position 153. 1 / 1
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Besides phosphorylation, the deubiquitinating enzyme BRCA1/BRCA2-containing complex subunit 3 (BRCC3) promotes an inflammasome activation by deubiquitinating NLRP3 at its LRR domain 153 .
BRCC3 deubiquitinates H2AC11. 1 / 1
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signor
Brcc36 regulates the abundance of lys(63)-linked ubiquitin chains at chromatin and that one of its substrates is diubiquitinated histone h2a

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
BRCC3 affects BRCA1
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BRCC3 inhibits BRCA1.
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BRCC3 inhibits BRCA1. 2 / 5
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The study has demonstrated that BRCC3 depletion prevents the formation of BRCA1 nuclear foci, and subsequently impairs the DNA repair pathway in response to DNA damage by ionizing radiation in breast cancer cells, suggesting that BRCC3 is referred as a potential therapeutic target for breast cancer [XREF_BIBR].

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Immunofluorescent staining of BRCA1 and gamma-H2AX indicates that BRCC36 depletion prevents the formation of BRCA1 nuclear foci in response to DNA damage in breast cancer cells.
BRCC3 activates BRCA1.
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BRCC3 activates BRCA1. 4 / 5
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The so called BRCA1-A complex comprises RAP80, Abraxas and CCDC98, the deubiquitinase BRCC36, BRCC45 and MERIT40, which are thought to target BRCA1 to IR induced foci through the interaction of RAP80 with polyubiquitin chains such as is thought to occur at histone gamma-H2AX [XREF_BIBR, XREF_BIBR] (see XREF_FIG).

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These results indicate that the two new subunits, BRCC36 and BRE, potentiate the E3 ligase activity of BRCA1 and BARD1.

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But beside the canonical role of deubiquitinating enzymes in antagonizing ubiquitin ligase activity, BRCC36 also enhances BRCA1 and BARD1 E3 ubiquitin ligase activity.

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Notably, BRCC36 depletion has been shown to impair activation of BRCA1 and to sensitise breast cancer cells to IR-induced apoptosis [146].
ABRAXAS2 affects BRCC3
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Previous structural studies have clearly shown how the BRISC subunit Abro1 binds to and allosterically activates the DUB activity of BRCC36 and how this heterodimer further self-associates to form a " superdimeric " assembly.

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Mechanism by which KIAA0157 supports BRCC36 catalytic function.

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Interestingly, although CCDC98 functions as an adaptor of BRCC36 and regulates BRCC36 activity in the nucleus, KIAA0157 mainly localizes in cytosol and activates BRCC36 in the cytoplasm.

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We pursued crystallization of BRCC36-KIAA0157 subcomplexes from different species (H. sapiens, G. gallus, X. tropicalis, D. rerio, C. floridanus and A. thaliana) to determine the structural basis for (1) how KIAA0157 supports the catalytic function of BRCC36, and (2) how super dimerization of the minimally active BRCC36 and KIAA0157 heterodimer is mediated.

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This likely reflects the fact that the mechanism by which KIAA0157 and Abraxas support BRCC36 will differ from how CSN6 and RPN8 support and regulate the function of CSN5 and RPN11.

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To understand how KIAA0157 supports the catalytic function of BRCC36, we set out to solve an inactive-state structure of BRCC36 in isolation.
BRCC3 affects NLRP3
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BRCC3 activates NLRP3.
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BRCC3 activates NLRP3. 5 / 5
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Regulation of oxidized LDL induced inflammatory process through NLRP3 inflammasome activation by the deubiquitinating enzyme BRCC36.

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The authors further suggested that the deubiquitylation of NLRP3 was critical for the inflammasome activation based on the facts that inhibiting BRCC3 could abolish NLRP3 inflammasome activation under a diverse range of classic " activation signals, " including K + efflux, ROS overproduction, and lysosomal destabilization.

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Moreover, USP7, USP47, and BRCC3 and ABRO can activate the NLRP3 inflammasome.

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The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson 's disease models.

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Deubiquitination of NLRP3 by the BRCA1 / BRCA2 containing complex subunit 3 (BRCC3) promoted NLRP3 inflammasome activity by preventing its degradation 39.
BRCC3 inhibits NLRP3.
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BRCC3 inhibits NLRP3. 3 / 3
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Knock-down of BRCC3 with shRNA lentivirus decreased NLRP3 neuronal inflammasome.

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BRCC3 knockdown leads to an increase in NLRP3 ubiquitination, and the DUB activity of BRCC3 is required for caspase-1 activation and IL-1beta processing, but not for LPS induced transcription of pro-IL-1beta or of NLRP3 itself XREF_BIBR.

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Functionally, we show that lentivirus mediated overexpression of WWP2 in murine macrophages inhibits NLRP3 inflammasome activation by decreasing BRCC3 protein level.
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In contrast, the knockdown of BRCC3 (BRCC3-KD) through the application of lentivirus mediated shRNA delivery system into OPCs suppressed OL differentiation by decreasing MBP expression and PLP production.

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In this study, we found depletion of BRCC36 promoted the differentiation and activation of osteoblast, and beta-catenin mediated this effect.

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BRCC3 siRNA promoted differentiation of osteoblasts and up-regulated beta-catenin After transfected with BRCC3 siRNA and cultured for 21 days, the cells were stained with ALP and ARS (XREF_FIG).

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Moreover, depletion of BRCC3 promoted osteogenic differentiation of osteoblast through up-regulated beta-catenin expression, whereas opposite effects were observed after BRCC3 overexpression.

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Results showed that XAV939 inhibited the ALP activation and formation of calcified nodules induced by BRCC3 siRNA, suggesting that beta-catenin signaling mediated the BRCC3 siRNA induced osteogenic differentiation (XREF_FIG).

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XAV939 reversed the BRCC3 siRNA induced osteogenic differentiation.
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Inhibition of beta-catenin reversed BRCC3 siRNA induced osteogenic differentiation To test the role of beta-catenin in BRCC3 siRNA actions, cells were treated with XAV939 to inhibit the activation of beta-catenin signaling.
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Additionally, the differentiation and beta-catenin expression were suppressed by BRCC3 overexpression.
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BRCC3 activates Cell Survival.
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Knockdown of BRCC3 increased the cell survival fraction, attenuated DNA damage repair and resulted in G2/M cell cycle arrest in radioresistant NPC cells.

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Since BRCC 3 is one of most regulated molecules by miR-US25-1, we speculated that the cell viability reduction might be caused by the BRCC 3 blockage.

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Our data showed that BRCC3 gene knockdown reduced the cell viability of TMZ treated U251 and A172 cells when compared to the relative TMZ treated mock cells.

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The inhibition of BRCC3 gene expression significantly reduces the cell viability and clonogenicity of U251 and A172 cells by TMZ treatment, indicating that BRCC3 can be treated as the target in order to enhance the sensitivity of glioma cells to TMZ.
BRCC3 inhibits Cell Survival.
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Furthermore, BRCC3 interference inhibited the cell viability, invasion and migration abilities of HeLa and SiHa cells via regulation of EMT progression and expression levels of Snai family members.
BRCC3 affects CTNNB1
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BRCC3 increases the amount of CTNNB1.
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BRCC3 increases the amount of CTNNB1. 3 / 3
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Depletion of BRCC3 promoted the activation of alkaline phosphatase and formation of calcified nodules in osteoblasts isolated from osteoporosis patients and up-regulated beta-catenin expression.

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Consistently, depletion of BRCC3 increased the level of beta-catenin and promoted osteogenic differentiation, and inhibitor XAV939 inhibited the BRCC3 induced osteogenic differentiation.

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Interestingly, we revealed that BRCC36 knockdown decreased beta-catenin expression in CRC cells, suggesting that binding between SHMT2 and BRCC36 may direct BRCC36 activity towards K63-Ub chains conjugated to beta-catenin in CRC cells.
BRCC3 decreases the amount of CTNNB1.
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Modified BRCC3 decreases the amount of CTNNB1. 2 / 2
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Additionally, BRCC3 overexpression significantly inhibited expressions of beta-catenin at both mRNA and protein levels (XREF_FIG).

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Additionally, the differentiation and beta-catenin expression were suppressed by BRCC3 overexpression.
BRCC3 activates CTNNB1.
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BRCC3 activates CTNNB1. 1 / 1
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BRCC3 siRNA promoted differentiation of osteoblasts and up-regulated beta-catenin After transfected with BRCC3 siRNA and cultured for 21 days, the cells were stained with ALP and ARS (XREF_FIG).
CD276 affects BRCC3
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CD276 increases the amount of BRCC3. 5 / 5
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In 2016, Sun et al[62] reported in their in vitro study that overexpression of B7-H3 upregulates BRCA1/BRCA2-containing complex subunit 3 (BRCC3) expression and antagonizes the anticancer activity of 5-fluorouracil (5-FU).
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Altogether, results suggest that BRCC3 may play a role in B7-H3-induced 5-Fu resistance, such that B7-H3 upregulates BRCC3 expression, enhancing DNA repair in colorectal cancer cells.

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Moreover, B7-H3 could upregulate BRCC3 or XRCC1 expression to antagonize DNA damage caused by 5-FU or L-OHP in CRC XREF_BIBR, XREF_BIBR.

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In addition, a few other mechanisms may also underlie B7H3 mediated chemoresistance : (1) B7H3 induces oxaliplatin resistance by increasing the expression of XRCC1 via PI3K and AKT pathway; (2) B7H3 also enhances cell resistance to chemotherapy by increasing the expression of BRCC3, which antagonizes DNA damage caused by 5-FU; (3) or via the activation of the PI3K and AKT pathway.

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B7-H3 upregulates BRCC3 expression, antagonizing DNA damage caused by 5-Fu.
BRCC3 affects TRAF2
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BRCC3 activates TRAF2. 5 / 5
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BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-kappaB Signaling Pathway Through Targeting TRAF2.
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Our results indicate that high BRCC3 expression activates NF-kappaB signaling by targeting TRAF2 for activation, which in turn facilitates tumorigenesis in bladder cancer.
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Here, we found that high expression of BRCC3 promoted tumorigenesis through targeting the TRAF2 protein.
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We found that BRCC3 increased the activation NF-κB signaling pathway together with the upstream molecules TNFR and TRAF2 (Figure 5A).
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BRCC3 binds to and synergizes with TRAF2 to activate NF-kappaB signaling.
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BRCC3 affects IL1B
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BRCC3 activates IL1B.
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BRCC3 activates IL1B. 4 / 4
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Besides, inhibition of BRCC3 blocked the increased secretion of IL-1beta.

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Since transduction of wild-type BRCC3, but not of the inactive mutant BRCC3 H122Q, rescued caspase-1 cleavage and IL-1beta secretion inhibited by BRCC3 KD, we conclude that BRCC3 regulates NLRP3 throu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Furthermore, BRCC3 knockdown was shown to reduce the ATP induced secretion of mature IL-1beta by in macrophages.

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Particularly, Benedicte et al. found that, knockdown of BRCC3 (a component of the BRISC complex) completely inhibited caspase-1 cleavage and IL-1beta secretion.
BRCC3 inhibits IL1B.
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BRCC3 inhibits IL1B. 1 / 1
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Since transduction of wild-type BRCC3, but not of the inactive mutant BRCC3 H122Q, rescued caspase-1 cleavage and IL-1beta secretion inhibited by BRCC3 KD, we conclude that BRCC3 regulates NLRP3 throu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
BRCC3 affects DNA repair
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BRCC3 activates DNA repair.
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Altogether, results suggest that BRCC3 may play a role in B7-H3-induced 5-Fu resistance, such that B7-H3 upregulates BRCC3 expression, enhancing DNA repair in colorectal cancer cells.

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Thus, the inhibition of BRCC3 expression may impair DNA repair mechanism in U251 and A172 cells, which can promotes sensitization of the two glioma cell lines to TMZ.
BRCC3 inhibits DNA repair.
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In addition, the deficiency of BRCC3 gene expression reduced the levels of DNA repair associated genes (i.e. BRCA1, BRCA2, RAD51 and FANCD2) in TMZ treated U251 and A172 cells, when compared to those detected in TMZ treated mock cells.
BRCC3 affects DNA Damage
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BRCC3 inhibits DNA Damage.
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In addition, a few other mechanisms may also underlie B7H3 mediated chemoresistance : (1) B7H3 induces oxaliplatin resistance by increasing the expression of XRCC1 via PI3K and AKT pathway; (2) B7H3 also enhances cell resistance to chemotherapy by increasing the expression of BRCC3, which antagonizes DNA damage caused by 5-FU; (3) or via the activation of the PI3K and AKT pathway.

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Moreover, B7-H3 could upregulate BRCC3 or XRCC1 expression to antagonize DNA damage caused by 5-FU or L-OHP in CRC XREF_BIBR, XREF_BIBR.

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B7-H3 upregulates BRCC3 expression, antagonizing DNA damage caused by 5-Fu.

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Knockdown of BRCC3 increased the cell survival fraction, attenuated DNA damage repair and resulted in G2/M cell cycle arrest in radioresistant NPC cells.
BRCC3 activates DNA Damage.
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Given the fact that BRCC3 (BRCC36) is essential for the protection of breast cancer cells from ionizing radiation induced DNA damage [XREF_BIBR], a high level of BRCC3 could protect U251 and A172 cells from TMZ induced cytotoxicity.
BRCC3 affects CASP1
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BRCC3 activates CASP1.
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BRCC3 activates CASP1. 4 / 4
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Particularly, Benedicte et al. found that, knockdown of BRCC3 (a component of the BRISC complex) completely inhibited caspase-1 cleavage and IL-1beta secretion.

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Therefore, we conclude that BRCC3 might be involved in regulating deubiquitination of NLRP3.Consistent with an activator of NLRP3 activity, knockdown of BRCC3 inhibited mature IL-1beta and activated c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Since transduction of wild-type BRCC3, but not of the inactive mutant BRCC3 H122Q, rescued caspase-1 cleavage and IL-1beta secretion inhibited by BRCC3 KD, we conclude that BRCC3 regulates NLRP3 throu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In addition, BRCC3 knockdown inhibited NLRP3 dependent, TLR independent cleaved caspase-1 secretion triggered by ATP in NG5 cells.
BRCC3 inhibits CASP1.
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BRCC3 inhibits CASP1. 1 / 1
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Since transduction of wild-type BRCC3, but not of the inactive mutant BRCC3 H122Q, rescued caspase-1 cleavage and IL-1beta secretion inhibited by BRCC3 KD, we conclude that BRCC3 regulates NLRP3 throu[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Hsa-miR-223-5p decreases the amount of BRCC3. 4 / 4
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biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
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Hsa-miR-190a-3p decreases the amount of BRCC3. 4 / 4
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biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available

biopax:mirtarbase
No evidence text available
BRCC3 affects NFkappaB
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BRCC3 binds to and synergizes with TRAF2 to activate NF-kappaB signaling.
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Our results indicate that high BRCC3 expression activates NF-kappaB signaling by targeting TRAF2 for activation, which in turn facilitates tumorigenesis in bladder cancer.
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BRCC3 Activated NF-kappaB Signaling Pathway via TRAF2.
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BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-kappaB Signaling Pathway Through Targeting TRAF2.
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Our findings showed BRCC3 plays a crucial role in facilitating the development and progression of bladder cancer.To reveal the way how BRCC3 promotes carcinogenesis, we analyzed BRCC3-deficient bladder cancer cell lines by RNA-Seq, and the data showed that the NF-κB inflammatory pathway was notably downregulated when BRCC3 was knockout.
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BRCC3 over-expression promoted tumorigenesis and was not associated with the enzymatic activity of BRCC3.
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BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-kappaB Signaling Pathway Through Targeting TRAF2.
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Here, we found that high expression of BRCC3 promoted tumorigenesis through targeting the TRAF2 protein.
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BRCC3 affects tat
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BRCC3 activates tat.
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BRCC3 activates tat. 3 / 3
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Further analysis showed that knockdown of SHMT1,2 or BRCC36 reduced Tat protein stability without affecting mRNA levels (XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY).

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Moreover, point mutation of multiple lysines in Tat, or knockdown of BRCC36 or SHMT1,2, was sufficient to prevent destruction of Tat by JIB-04.

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Taken together, these data strongly suggest that SHMT2 and BRCC36 and BRISC cooperate to rescue Tat from destruction through removal of K63Ub.
BRCC3 inhibits tat.
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BRCC3 inhibits tat. 1 / 1
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Taken together, these data suggested a model through which SHMT2 and BRCC36 act to reverse K63Ub of Tat, thereby preventing its destruction by autophagy (XREF_FIG).
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We found that BRCC3 increased the activation NF-κB signaling pathway together with the upstream molecules TNFR and TRAF2 (Figure 5A).
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BRCC3 Activated NF-kappaB Signaling Pathway via TRAF2.
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BRCC3 Promotes Tumorigenesis of Bladder Cancer by Activating the NF-kappaB Signaling Pathway Through Targeting TRAF2.
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Furthermore, TNFα and phospho-P65 was decreased while the level of IκBα was increased in the BRCC3 group, which confirmed that the abolition of BRCC3 inhibited the NF-κB signaling pathway (Figure 6E).
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BRCC3 activates angiogenesis.
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Knockdown of this gene resulted in angiogenesis defects, which were also rescued by endothelium specific expression of BRCC3.

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Here, we showed that most RNF213- and BRCC3 associated miRNAs were elevated in serum of MMD patients, repressed RNF213 and BRCC3 protein expression in HBMVEC, and modulated HBMVEC angiogenesis.

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We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium specific expression of brcc3.
BRCC3 inhibits angiogenesis.
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Morpholino mediated knockdown of the BRCC3 ortholog in zebrafish led to defective angiogenesis that was rescued by endothelial specific expression of brcc3, strongly suggesting that this deubiquitinat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
BRCC3 affects STAT1
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BRCC3 activates STAT1.
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BRCC3 activates STAT1. 3 / 3
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BRCC36 functions noncatalytically to promote antiviral response by maintaining STAT1 protein stability.

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For example, BRCC36 functions noncatalytically by recruiting USP13 to counteract the SMURF1-mediated degradation of STAT1, and this effect enhances the stability of STAT1 and improves host antiviral efficiency (110).

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Supplementing BRCC36 enhanced antiviral response of allo-HSCT mice by maintaining STAT1 stability.
BRCC3 decreases the amount of STAT1.
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BRCC3 decreases the amount of STAT1. 1 / 1
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More specifically, BRCC36 deficiency leads to a rapid downregulation of STAT1 during viral infection, whereas complementation by BRCC36 can rescue the STAT1 expression levels and suppress virus infection (110).
BRCC3 affects NUMA1
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BRCC3 inhibits NUMA1.
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BRCC3 inhibits NUMA1. 1 / 2
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However, in BRCC36 silenced cells, a large proportion of NuMA aggregates was retained in the peripheral areas distant from the spindle poles (XREF_FIG; 25-30 min), and supernumerary poles were formed, indicating that depletion of BRCC36 decreases the incorporation of NuMA into spindle poles during mitosis, presumably by aberrant dynamic interaction between NuMA and its partner dynein.
BRCC3 activates NUMA1.
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BRCC3 activates NUMA1. 1 / 2
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Immunoprecipitation revealed that depletion of ABRO1 or BRCC36 increased the interaction of NuMA with dynein, as well as with importin-beta in HeLa cells (XREF_FIG), indicating that BRISCs negatively regulate the association of NuMA with dynein and importin-beta.

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Supporting this model, BRCC36 depletion increases DSB-associated conjugated ubiquitin and 53BP1 accumulation at DSB sites [189].

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BRCC36 downregulates DSB signaling by removing K63 linked polyubiquitin.

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Supporting this model, BRCC36 depletion increases DSB associated conjugated ubiquitin and 53BP1 accumulation at DSB sites [189].

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Supporting this model, BRCC36 depletion increases DSB associated conjugated ubiquitin and 53BP1 accumulation at DSB sites XREF_BIBR.
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Hsa-miR-6867-5p decreases the amount of BRCC3. 3 / 3
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Hsa-miR-574-5p decreases the amount of BRCC3. 3 / 3
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Hsa-miR-511-3p decreases the amount of BRCC3. 3 / 3
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Hsa-miR-5011-5p decreases the amount of BRCC3. 3 / 3
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Hsa-miR-3121-5p decreases the amount of BRCC3. 3 / 3
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Hsa-miR-1277-5p decreases the amount of BRCC3. 3 / 3
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BRCC3 gene knockdown through lentivirus mediated gene knockdown approach not only significantly reduced the clonogenic and migratory abilities of U251 and A172 cells, but also enhanced their sensitization to TMZ.

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Our data showed that BRCC3 gene knockdown reduced the cell viability of TMZ treated U251 and A172 cells when compared to the relative TMZ treated mock cells.

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Accordingly, we examined if the depletion of BRCC3 promotes TMZ induced cytotoxicity in U251 and A172 cells.
BRCC3 affects BRCC3
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BRCC3 decreases the amount of BRCC3. 2 / 3
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Consistently, BRCC3 siRNA treatment of MDA-MB 231 cells caused decreased expression of BRCC3 and p-ERK.

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Here, we showed that most RNF213- and BRCC3 associated miRNAs were elevated in serum of MMD patients, repressed RNF213 and BRCC3 protein expression in HBMVEC, and modulated HBMVEC angiogenesis.
SHMT2 affects BRCC3
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SHMT2 activates BRCC3. 2 / 2
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Cytosolic SHMT2 was known to direct the BRCC36 containing complex (BRISC, a complex with deubiquitination activity) to deubiquitinate type I IFN receptor chain 1 (IFNalphaR1) and thus decrease the internalization and increase the stability of IFNalphaR1.

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Cytoplasmic SHMT2 directs BRCC36 isopeptidase complex (BRISC) activity at K63-Ub chains combined with the type 1 interferon receptor chain 1 (IFNAR1).
SHMT2 bound to BRCC3 activates BRCC3. 1 / 1
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Interestingly, we revealed that BRCC36 knockdown decreased beta-catenin expression in CRC cells, suggesting that binding between SHMT2 and BRCC36 may direct BRCC36 activity towards K63-Ub chains conjugated to beta-catenin in CRC cells.
BRCC3 affects TP53BP1
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BRCC3 activates TP53BP1.
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BRCC3 activates TP53BP1. 2 / 2
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XREF_BIBR Importantly co-depletion of POH1 and BRCC36 did not elicit 53BP1 foci larger than POH1 depletion alone, suggesting these DUBs act in the same mechanistic pathway to restrict 53BP1 assemblies.

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Co-depletion of POH1 and RAP80, BRCC36 or ABRAXAS allows establishment of the 53BP1 and ubiquitin chain-devoid core.
BRCC3 decreases the amount of TP53BP1.
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BRCC3 decreases the amount of TP53BP1. 1 / 1
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This complex also contains K63-Ub-specific DUB, BRCC36, able to hydrolyse K63-chains and restrict the amount of 53BP1 at damaged chromatin.
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The cell migration and invasion of U251 and A172 cells are also impaired by BRCC3 knockdown.

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The cell invasion of the two cell lines was also diminished by the inhibition of BRCC3 expression.

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Furthermore, BRCC3 interference inhibited the cell viability, invasion and migration abilities of HeLa and SiHa cells via regulation of EMT progression and expression levels of Snai family members.
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But beside the canonical role of deubiquitinating enzymes in antagonizing ubiquitin ligase activity, BRCC36 also enhances BRCA1 and BARD1 E3 ubiquitin ligase activity.

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These results indicate that the two new subunits, BRCC36 and BRE, potentiate the E3 ligase activity of BRCA1 and BARD1.
BRCC3 bound to BABAM2 activates E3_Ub_ligase. 1 / 1
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The interaction between BRE and BRCC36 has been reported to enhance the E3 ligase activity of BRCA1-BARD1 in a BRCC complex XREF_BIBR.
Hsa-miR-567 affects BRCC3
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Hsa-miR-567 decreases the amount of BRCC3. 2 / 2
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Hsa-miR-297 affects BRCC3
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Hsa-miR-297 decreases the amount of BRCC3. 2 / 2
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Dibutyl phthalate decreases the amount of BRCC3. 2 / 2
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ICP0 affects BRCC3
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ICP0 inhibits BRCC3. 2 / 2
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HSV is particularly effective in this antagonism, with HSV ICP0 promoting degradation of the host deubiquitinase BRCC36, resulting in downregulation of IFNAR1 in a variety of human and mouse cell lines in vitro [140] .

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HSV-1-encoded ICP0 degrades the host deubiquitinase BRCC36 to antagonize interferon antiviral response.
GABPB2 affects BRCC3
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GABPB2 decreases the amount of BRCC3. 2 / 2
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GABPA affects BRCC3
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GABPA decreases the amount of BRCC3. 2 / 2
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Although the suppressive role of BRCC36 in RNF8 dependent DDR suggests that BRCC36 promotes HR, the depletion of BRCC36 increases HR efficiency [XREF_BIBR].

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Interestingly, the depletion of BRCC36 increases HR, which goes against the suppressive role of BRCC36 in RNF8 dependent DDR that should suggest that BRCC36 promotes HR.
BRCC3 affects cell growth
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Moreover, the depletion of BRCC3 gene expression decreases the cell growth and clonogenic ability of U251 and A172 cells.
BRCC3 affects RNF8
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BRCC3 inhibits RNF8. 2 / 2
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In this complex, BRCC36 works together with the proteins NBA1, ABRO1, ABRA1 and BRCC45 in cleaving K63 linked ubiquitin chains and therefore seems to antagonize the ubiquitinating function of UBC13, RNF8 and RNF168.

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BRCC36 and POH1 antagonize the actions of RNF8 and RNF168, hydrolyzing the K63 linkages that promote 53BP1 recruitment.
BRCC3 affects RNF168
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BRCC3 inhibits RNF168. 2 / 2
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In this complex, BRCC36 works together with the proteins NBA1, ABRO1, ABRA1 and BRCC45 in cleaving K63 linked ubiquitin chains and therefore seems to antagonize the ubiquitinating function of UBC13, RNF8 and RNF168.

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BRCC36 and POH1 antagonize the actions of RNF8 and RNF168, hydrolyzing the K63 linkages that promote 53BP1 recruitment.
BRCC3 affects BARD1
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BRCC3 activates BARD1. 2 / 2
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These results indicate that the two new subunits, BRCC36 and BRE, potentiate the E3 ligase activity of BRCA1 and BARD1.

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But beside the canonical role of deubiquitinating enzymes in antagonizing ubiquitin ligase activity, BRCC36 also enhances BRCA1 and BARD1 E3 ubiquitin ligase activity.
Abraxas affects BRCC3
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Abraxas activates BRCC3. 2 / 2
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This likely reflects the fact that the mechanism by which KIAA0157 and Abraxas support BRCC36 will differ from how CSN6 and RPN8 support and regulate the function of CSN5 and RPN11.

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Abraxas mainly localizes in the nucleus, mediating the interaction of BRCC36 with BRCA1.
Bisphenol A affects BRCC3
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Bisphenol A increases the amount of BRCC3.
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Bisphenol A increases the amount of BRCC3. 1 / 1
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Bisphenol A decreases the amount of BRCC3.
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Bisphenol A decreases the amount of BRCC3. 1 / 1
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Benzo[a]pyrene increases the amount of BRCC3.
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Benzo[a]pyrene increases the amount of BRCC3. 1 / 1
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Benzo[a]pyrene decreases the amount of BRCC3.
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Benzo[a]pyrene decreases the amount of BRCC3. 1 / 1
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TCHH affects BRCC3
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TCHH inhibits BRCC3.
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TCHH inhibits BRCC3. 1 / 1
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Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome, Associated-molecule-with-the-SH3-Domain-of-STAM (AMSH), which regulates ubiquitin dependent sorting of cell-surface receptors, and Brcc36, a K63 specific deubiquitnase of BRCC36 containing isopeptidase complex (BRISC) and BRCA1, BRCA2, and containing complex (BRCC).
TCHH activates BRCC3.
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TCHH activates BRCC3. 1 / 1
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We showed here that the reduced forms of THL and other DTPs act as Zn 2+ chelators to inhibit the JAMM metalloproteases Rpn11, Csn5 AMSH, and Brcc36.
SYVN1 affects BRCC3
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SYVN1 inhibits BRCC3.
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SYVN1 inhibits BRCC3. 1 / 1
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SYVN1-mediated BRCC3 down-regulation promoted NLRP3 ubiquitination and reduced pro-inflammatory cytokine secretion.
SYVN1 deubiquitinates BRCC3.
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SYVN1 leads to the deubiquitination of BRCC3. 1 / 1
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Overexpressing SYVN1 promoted the ubiquitination and degradation of BRCC3 and reduced the secretion of pro-inflammatory cytokines in HG-induced Müller cells.
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Plant Extracts increases the amount of BRCC3.
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Plant Extracts increases the amount of BRCC3. 1 / 1
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Plant Extracts decreases the amount of BRCC3.
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Plant Extracts decreases the amount of BRCC3. 1 / 1
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BRCC3 affects cell death
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BRCC3 inhibits cell death.
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Moreover, BRCC3 gene knockdown promoted the cell death of U251 and A172 cells in response to BCNU (XREF_SUPPLEMENTARY).
BRCC3 activates cell death.
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Furthermore, exogenous BRCC3 expression was associated with a delay in etoposide induced cell death and an increase in cell proliferation.
BRCC3 affects TNF
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BRCC3 inhibits TNF.
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BRCC3 inhibits TNF. 1 / 1
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In addition, Real-time PCR analyses indicated that the ablation of BRCC3 reduced the expression of the NF-κB signaling down-stream genes including cIAP2, TNFα, and ICAM (Figure 4F).
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BRCC3 activates TNF.
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BRCC3 activates TNF. 1 / 1
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We found that the downregulation of BRCC3 led to a specific and strong blockage of IL-1beta release triggered by ATP, while it had no effect on the NLRP3 independent TNF-alpha and IL-6 secretion induc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
BRCA1 affects BRCC3
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BRCA1 inhibits BRCC3.
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BRCA1 inhibits BRCC3. 1 / 1
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While truncation of BARD1 did not affect the association of any of the components of the complex, BRCA1 truncation completely abrogated the association of BRCC36 and BRE and reduced the association of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
BRCA1 activates BRCC3.
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BRCA1 activates BRCC3. 1 / 1
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The experiments were performed in triplicates comparing the cells treated with siRNAs against BRCC36 or BRE, to those treated with siRNAs against BRCA1 and control siRNAs.
Urethane affects BRCC3
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Urethane decreases the amount of BRCC3. 1 / 1
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Torcetrapib affects BRCC3
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Torcetrapib increases the amount of BRCC3. 1 / 1
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Sunitinib affects BRCC3
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Sunitinib decreases the amount of BRCC3. 1 / 1
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Sodium dichromate increases the amount of BRCC3. 1 / 1
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Resveratrol affects BRCC3
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Resveratrol decreases the amount of BRCC3. 1 / 1
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We further identified that the ROS overproduction and mtDNA oxidative damage with upregulated deubiquitinase BRCC36, a potential molecular mechanism by which ocular surface epithelium initiates innate immune response to the environmental stress.
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Promethazine decreases the amount of BRCC3. 1 / 1
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Potassium chromate decreases the amount of BRCC3. 1 / 1
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Polyphenol affects BRCC3
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Polyphenol decreases the amount of BRCC3. 1 / 1
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Piroxicam affects BRCC3
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Piroxicam decreases the amount of BRCC3. 1 / 1
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Pentachlorophenol increases the amount of BRCC3. 1 / 1
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Ochratoxin A decreases the amount of BRCC3. 1 / 1
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Nickel sulfate decreases the amount of BRCC3. 1 / 1
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Nickel monoxide decreases the amount of BRCC3. 1 / 1
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Mono(2-ethylhexyl) phthalate decreases the amount of BRCC3. 1 / 1
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Methylmercury chloride decreases the amount of BRCC3. 1 / 1
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Methapyrilene decreases the amount of BRCC3. 1 / 1
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Hsa-miR-92a-3p decreases the amount of BRCC3. 1 / 1
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Hsa-miR-7977 decreases the amount of BRCC3. 1 / 1
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Hsa-miR-7705 decreases the amount of BRCC3. 1 / 1
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Hsa-miR-7162-5p decreases the amount of BRCC3. 1 / 1
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Hsa-miR-6849-3p decreases the amount of BRCC3. 1 / 1
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Hsa-miR-6715b-5p decreases the amount of BRCC3. 1 / 1
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Hsa-miR-670-3p decreases the amount of BRCC3. 1 / 1
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Hsa-miR-596 affects BRCC3
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Hsa-miR-596 decreases the amount of BRCC3. 1 / 1
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Hsa-miR-573 affects BRCC3
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