Poly-(ADP-ribose) polymerase inhibitors (PARPi) selectively kill breast and ovarian cancers with defects in homologous recombination (HR) caused by BRCA1/2 mutations. There is also clinical evidence for the utility of PARPi in breast and ovarian cancers without BRCA mutations, but the underlying mechanism is not clear. Here, we report that the deubiquitylating enzyme USP15 affects cancer cell response to PARPi by regulating HR. Mechanistically, USP15 is recruited to DNA double-strand breaks (DSBs) by MDC1, which requires the FHA domain of MDC1 and phosphorylated Ser678 of USP15. Subsequently, USP15 deubiquitinates BARD1 BRCT domain, and promotes BARD1-HP1γ interaction, resulting in BRCA1/BARD1 retention at DSBs. USP15 knockout mice exhibit genomic instability in vivo. Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells. Thus, our results identify a novel regulator of HR, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420636 | PMC |
| http://dx.doi.org/10.1038/s41467-019-09232-8 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Ailanthone induces triple-negative breast cancer cells death involving the inhibition of OTUB1-mediated ERRα deubiquitylation.
J Adv Res
January 2025
Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518020, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address:
Introduction: Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, and effective therapeutic strategies are needed. Estrogen-related receptor alpha (ERRα) is considered a promising target for managing TNBC.
Objectives: Here, we aimed to screen natural products to find downregulator of ERRα and elucidate its mechanism of action.
ERK-USP9X-coupled regulation of thymidine kinase 1 promotes both its enzyme activity-dependent and its enzyme activity-independent functions for tumor growth.
Nat Struct Mol Biol
January 2025
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Thymidine kinase 1 (TK1), a crucial enzyme in DNA synthesis, is highly expressed in various cancers. However, the mechanisms underlying its elevated expression and the implications for tumor metabolism remain unclear. Here we demonstrate that activation of growth factor receptors enhances TK1 expression.
View Article and Find Full Text PDFCabozantinib Selectively Induces Proteasomal Degradation of p53 Somatic Mutant Y220C and Impedes Tumor Growth.
J Biol Chem
January 2025
Department of Hepatopancreatobiliary Surgery, Suzhou Ninth Hospital Affiliated to Soochow University; Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University; Jiangsu, China. Electronic address:
Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors, and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment.
View Article and Find Full Text PDFHOXA3 activates USP15 to suppress autophagy and promote M2-type macrophage polarization in renal cell carcinoma via facilitating the deubiquitination of SQSTM1.
Am J Physiol Cell Physiol
December 2024
Department of Urology, Xiangya Hospital, Central South University, Changsha 410000, Hunan Province, P.R. China.
The disease burden of renal cell carcinoma (RCC) has decreased in recent years with advances in treatment, but its pathogeny still remains elusive. We aim to study the role of HOXA3/USP15/SQSTM1 axis on autophagy and M2-type macrophage polarization in RCC. In this study, cell apoptosis and proliferation were assessed by flow cytometry and CCK-8.
View Article and Find Full Text PDFUSP35 promotes breast cancer progression by regulating PFK-1 ubiquitination to mediate glycolysis.
Am J Physiol Cell Physiol
February 2025
Department of Breast Surgery, Fujian Medical University Union Hospital, Fuzhou, People's Republic of China.
Ubiquitin-specific protease 35 () was found to be involved in various tumor progression, but its role in breast cancer remains largely unknown. USP35 mRNA and protein expression in breast cancer tissues and cells were evaluated by quantitative real-time PCR and Western blot, respectively. Subsequently, flow cytometry and 5-ethynyl-2'-deoxyuridine labeling were used to evaluate breast cancer cell apoptosis and proliferation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!