USP45 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 45
HGNC Gene Symbol
USP45
Identifiers
hgnc:20080 NCBIGene:85015 uniprot:Q70EL2
Orthologs
mgi:101850 rgd:1310976
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP45
Number of Papers
102 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

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP45using 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

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP45 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
USP45 deubiquitinates ERCC1. 10 / 12
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It was shown that USP45 interacts with and deubiquitinates the excision repair cross complementation group 1 (ERCC1) subunit of the XPF-ERCC1 DNA repair nuclease which has role in the TC-NER of UV induced DNA damage [XREF_BIBR, XREF_BIBR].

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As expected, the catalytically inactive USP45 [Cys199Ala] mutant also failed to deubiquitylate ERCC1 (Fig XREF_FIG C, XREF_SUPPLEMENTARY).

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Upon UV exposure, USP45 interacts with ERCC1-XPF but the USP45 mutant (Asp25Ala, Glu26Ala) that is catalytically active but that can not bind to ERCC1 failed to deubiquitinate ERCC1.

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These data therefore indicate that likely the ubiquitylation of ERCC1, which is reversed by USP45, controls an aspect of ERCC1 function other than regulating its stability.

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In this light, we observed that 5 other DUBs tested (AMSH, Cezanne, OTUB1, UCHL1 and USP27X) failed to deubiquitylate ERCC1 under conditions that wild-type USP45 deubiquitylated ERCC1 (Supplementary Fig S5C).

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The major role of ERCC1 deubiquitination by USP45 has been speculated to enable ERCC1-XPF to gain access to DNA damage sites.

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Both mass spectrometry and yeast two-hybrid system identify that USP45 interacts with ERCC1, and it was also demonstrated that USP45 deubiquitinates ERCC1 [55].

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USP45 targeting ERCC1

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ERCC1 can be deubiquitinated by USP45, which promotes XPF-ERCC1 recruitment to sites of DNA damage [XREF_BIBR].

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This, coupled with the report that inactivating the USP45 protein that deubiquitinates ERCC1 in human myelogenous leukaemia and osteosarcoma cells leads to reduced levels of NER and increased sensitivity to UV irradiation [XREF_BIBR], suggests that our therapeutic strategy is likely applicable to a wide range of human cancers.
Mutated USP45 deubiquitinates ERCC1. 2 / 2
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Importantly, we find that the USP45 mutant [Asp25Ala, Glu26Ala] that is catalytically active but that can not bind to ERCC1 (Supplementary Fig S5A) failed to deubiquitylate ERCC1 in vitro, indicating that specific interaction between ERCC1 and USP45 is essential to trigger deubiquitylation.

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Importantly, the USP45 mutant [Asp25Ala, Glu26Ala] that displays the same intrinsic catalytic activity as wild-type USP45 when assayed using a generic ubiquitin-rhodamine substrate (XREF_SUPPLEMENTARY), but that can not bind ERCC1, failed to deubiquitylate ERCC1 in parallel experiments (Fig XREF_FIG C, XREF_SUPPLEMENTARY).
USP45 deubiquitinates ERCC1 on lysine. 1 / 1
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biopax:reactome
No evidence text available

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
Peptide affects USP45
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To overcome this inconvenience, we then constructed a novel recombinant strain, L. lactis MG1363 harboring an expression plasmid pSECN, in which the n gene was fused with the coding sequence of USP45 signal peptide and was controlled by the constitutive L. lactis promoter P59.

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Our data confirmed that the use of sp6 anchor in addition to usp45 signal peptide and interval sequence can efficiently display LTB on the surface of L. lactis.

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shuttle vector: 1) L. lactis expressing secreted proteins was constructed with recombinant pTRKH2 (secreted-protein plasmid) carrying the Usp45 signal peptide (SPUsp45), nontoxic adjuvanted tetanus toxin fragment C (TETC), and 14 of the 38 C-terminal repeats (14CDTA) of nontoxic C. difficile toxin A (TcdA); and 2) L. lactis expressing secreted and membrane proteins was constructed with recombinant pTRKH2 (membrane-anchored plasmid) carrying SPUsp45, TETC, 14CDTA, and the cell wall-anchored sequence of protein M6 (cwaM6).

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P1 represents the constitutive promoter; SD, Shine-Dalgarno sequence; SS, first codons of the Usp45 signal peptide fused to the psaA gene.

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P1 represents the constitutive promoter; SD, Shine-Dalgarno sequence; SS, first codons of the Usp45 signal peptide fused to the psaA gene.Fig.

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A new VP1 (SPVP1), which was codon optimized with L. lactis, was synthesized by Nanjing GenScript Co. Ltd and then incorporated into pUC57 at the NcoI restriction site and contained a secretory Usp45 signal peptide (SPusp45) at the N terminus of the VP1 gene and the HindIII restriction site at the C terminus.

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Substantially higher levels of the fusion proteins (four- to six-fold) were secreted by the clones possessing Lactobacillus brevis SlpA signal peptide than by those possessing L. lactis Usp45 signal peptide.

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The psaA gene was cloned into the pT1NX vector PstI site, which produced a fusion of a truncated usp45 signal peptide carried by the vector to the PsaA sequence (Fig. 1), under the control of a constitutive promoter.

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P values < 0.05 were considered to be significant.The food-grade expression vector pNZ-SECF1S1 harboring the nisin-inducible promoter (PnisA) and Usp45 signal peptide was constructed.

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In early work in the field, Dieye et al. [27] showed that replacement of the M6 signal peptide with the Usp45 signal peptide from L. lactis doubled the amount of a staphylococcal nuclease reporter protein (NucA) that was successfully anchored to the cell wall [27] .
USP45 affects ERCC1
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USP45 activates ERCC1.
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USP45 activates ERCC1. 3 / 4
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Moreover, expression of wild-type USP45, but not catalytically deficient USP45 [Cys199Ala] mutant in these cells, restored the number of spontaneous ERCC1 foci almost to the level seen in wild-type U2OS cells (Fig XREF_FIG A and B).

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USP45 targeting ERCC1.

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Expression of wild-type USP45, but not the catalytically deficient USP45 [Cys199Ala] mutant in USP45 knockout U2OS cells, restored the number of DNA damage induced ERCC1 foci to levels observed in wild-type cells (Fig XREF_FIG A and B).
USP45 inhibits ERCC1.
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USP45 inhibits ERCC1. 1 / 2
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Restoring expression of wild-type USP45 in knockout U2OS cells markedly lowered the high molecular weight species of ERCC1 (Fig XREF_FIG B).
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Valproic acid increases the amount of USP45. 2 / 2
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Bisphenol A affects USP45
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Bisphenol A increases the amount of USP45.
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Bisphenol A increases the amount of USP45. 1 / 1
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Bisphenol A decreases the amount of USP45.
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Bisphenol A decreases the amount of USP45. 1 / 1
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17alpha-ethynylestradiol increases the amount of USP45.
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17alpha-ethynylestradiol increases the amount of USP45. 1 / 1
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17alpha-ethynylestradiol decreases the amount of USP45.
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17alpha-ethynylestradiol decreases the amount of USP45. 1 / 1
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Vorinostat affects USP45
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Vorinostat increases the amount of USP45. 1 / 1
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Vinclozolin affects USP45
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Vinclozolin increases the amount of USP45. 1 / 1
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Trichostatin A increases the amount of USP45. 1 / 1
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Sunitinib affects USP45
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Sunitinib increases the amount of USP45. 1 / 1
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Pirinixic acid decreases the amount of USP45. 1 / 1
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Phlorizin affects USP45
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Phlorizin decreases the amount of USP45. 1 / 1
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Paracetamol affects USP45
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Paracetamol increases the amount of USP45. 1 / 1
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Mono(2-ethylhexyl) phthalate decreases the amount of USP45. 1 / 1
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Mitomycin C affects USP45
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We also explored how USP45 knockout impacts on gamma-H2AX foci induced by MMC.
Methylmercury chloride decreases the amount of USP45. 1 / 1
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Methyl methanesulfonate increases the amount of USP45. 1 / 1
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Manganese(II) chloride decreases the amount of USP45. 1 / 1
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Manganese atom decreases the amount of USP45. 1 / 1
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Ionomycin affects USP45
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Ionomycin increases the amount of USP45. 1 / 1
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Hsa-miR-6873-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-6783-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-665 affects USP45
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Hsa-miR-665 decreases the amount of USP45. 1 / 1
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Hsa-miR-630 affects USP45
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Hsa-miR-630 decreases the amount of USP45. 1 / 1
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Hsa-miR-526a decreases the amount of USP45. 1 / 1
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Hsa-miR-523-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-522-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-520g-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-520c-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-519c-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-519b-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-519a-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-518f-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-518e-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-518d-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-4777-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-4668-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-3662 decreases the amount of USP45. 1 / 1
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Hsa-miR-32-5p decreases the amount of USP45. 1 / 1
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Hsa-miR-3149 decreases the amount of USP45. 1 / 1
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Hsa-miR-3148 decreases the amount of USP45. 1 / 1
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Hsa-miR-3145-3p decreases the amount of USP45. 1 / 1
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Hsa-miR-192-5p decreases the amount of USP45. 1 / 1
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Hsa-let-7f-5p decreases the amount of USP45. 1 / 1
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Galactose affects USP45
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We also show that the usp45 promoter is highly activated by galactose.
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Formaldehyde decreases the amount of USP45. 1 / 1
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Folic acid affects USP45
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Folic acid decreases the amount of USP45. 1 / 1
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Doxorubicin affects USP45
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Doxorubicin decreases the amount of USP45. 1 / 1
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Dioxygen affects USP45
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Dioxygen increases the amount of USP45. 1 / 1
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Choline affects USP45
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Choline decreases the amount of USP45. 1 / 1
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Bortezomib affects USP45
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Bortezomib increases the amount of USP45. 1 / 1
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We also show that the usp45 promoter is highly activated by galactose.
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Aflatoxin B1 increases the amount of USP45. 1 / 1
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USP45 affects sacA
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USP45 activates sacA. 1 / 1
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Removal of the USP45 secretion peptide allowed a soluble and functional invertase to be expressed intracellularly in L. lactis.
USP45 affects plasmin
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USP45 increases the amount of plasmin. 1 / 1
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Expression of the plasmin gene driven by the promoter and complete signal sequence of the lactococcal usp45 gene resulted in efficient plasmin secretion in strain BPL420.
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The Usp45 secretion and spaX (S. aureus protein A) anchor signals efficiently promote the localization of FNIII 7-10 in the bacterial membrane.
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Fusion of the usp45 promoter region and various parts of the leader sequence to an amyS gene devoid of its signal sequence, showed that in Escherichia coli the first 19, 20, and 27 residues of the Usp45 leader are able to direct alpha-amylase secretion.
USP45 affects LCN2
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USP45 activates LCN2. 1 / 1
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Construction of Lcn2 under the P1 promoter allows for constitutive expression, whereas USP45 encodes for the sequence signal to drive the secretion of Lcn2 from L. lactis.
USP45 affects DNA Damage
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Taken together, these data indicate that USP45 localises at sites of UV induced DNA damage, and at intra- and interstrand cross-links, and that USP45 is required, like ERCC1 for efficient NER.
SPINK1 affects USP45
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SPINK1 activates USP45. 1 / 1
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The psaA gene was cloned into the pT1NX vector PstI site, which produced a fusion of a truncated usp45 signal peptide carried by the vector to the PsaA sequence (Fig. 1), under the control of a constitutive promoter.
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L-methionine decreases the amount of USP45. 1 / 1
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Cuprizone affects USP45
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Cuprizone decreases the amount of USP45. 1 / 1
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Casp14 affects USP45
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Casp14 activates USP45. 1 / 1
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In agreement with these clinical findings, the LL-IL35-treated mice had markedly reduced Ly-6G + CD11b + cells (neutrophils) infiltrating the joints (Figure 2A ) representing a 7-and 5-fold reduction compared to The synthetic insert encodes in order: the usp45 secretion peptide genetically fused in-frame to the p35 subunit, a short flexible linker, fused to the EBI3.
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