The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-03-15

AUTHORS

Yihan Peng, Qingchao Liao, Wei Tan, Changmin Peng, Zhaohua Hu, Yali Chen, Zhuqing Li, Jing Li, Bei Zhen, Wenge Zhu, Xiangpan Li, Yi Yao, Qibin Song, Chengsheng Liu, Xiangdong Qi, Fuchu He, Huadong Pei

ABSTRACT

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. More... »

PAGES

1224

References to SciGraph publications

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    10

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-019-09232-8

    DOI

    http://dx.doi.org/10.1038/s41467-019-09232-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112767650

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30874560


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