Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCA1 regulates multiple cellular pathways that maintain genomic stability including cell cycle checkpoints, DNA repair, protein ubiquitination, chromatin remodelling, transcriptional regulation and apoptosis. Receptor-associated protein 80 (RAP80) helps recruit BRCA1 to double-strand breaks (DSBs) through the scaffold protein CCDC98 (Abraxas) and facilitates DNA damage response (DDR). However, the regulation of RAP80-BRCA1 complex is still unclear. Here we report that a deubiquitinase, USP13, regulates DDR by targeting RAP80. Mechanistically, USP13 is phosphorylated by ATM following DNA damage which, in turn, facilitates its DSB localization. USP13, in turn, deubiquitinates RAP80 and promotes RAP80 recruitment and proper DDR. Depleting or inhibiting USP13 sensitizes ovarian cancer cells to cisplatin and PARP inhibitor (olaparib) while overexpression of USP13 renders ovarian cancer cells resistant to chemotherapy. Overall, we identify USP13 as a regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination axis dynamically regulates RAP80-BRCA1 complex foci formation and function.
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PMID:USP13 regulates the RAP80-BRCA1 complex dependent DNA damage response. 2856 38

Esophageal squamous cell carcinoma (ESCC) is the most popular pathology of esophageal cancer (EC) in China, especially in Henan province, mid-east of China. Presently, targeting DNA damage repair (DDR) factors is a promising approach for cancer therapy. Our group has been focusing on exploring the DDR factors overexpressed in ESCC tissues to provide potential targets for therapies for many years. RAP80/UIMC1 (ubiquitin interaction motif containing 1), one of those DDR factors we tested, was highly overexpressed in ESCC tissues compared with adjacent normal tissues. Moreover, the RAP80 mRNA level was validated to be an independent prognosis biomarker for the overall survival time of ESCC patients. The following biological assays revealed that it promoted cell proliferation both in vitro and in vivo, inhibited cell apoptosis at both early and late stages, and participated in G2/M checkpoint regulation. Even though studies have reported that ATM phosphorylates RAP80 at different serine sites upon DNA damage, the reversal regulation of RAP80 on the activity of ATM has never been investigated. In the study, mechanism explorations revealed that RAP80 positively regulated the ATM activity via proteasome-ubiquitination pathway to promote the transition of G2/M phase in cell cycle. By examining a number of E3 ubiquitination ligases (Ub) and deubiquitination (DUb) enzymes, we found that RAP80 positively regulated the stability of USP13 to promote cell proliferation of EC cells. Moreover, inhibition of RAP80 greatly sensitized EC cells to ATM inhibitor KU-55933, triggering a potential combination of RAP80 inhibitors and ATM inhibitors to enhance the therapeutic efficiency of ESCC patients for the clinicians.
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PMID:RAP80 is an independent prognosis biomarker for the outcome of patients with esophageal squamous cell carcinoma. 2939 16