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ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability.

ABSTRACT: DNA double-strand break (DSB) repair by homologous recombination (HR) is essential for ensuring genome stability. Abnormal spindle-like microcephaly-associated (ASPM) gene encodes a spindle protein that is commonly implicated in primary microcephaly. We found that ASPM is recruited to sites of DNA damage in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ligase HERC2, preventing HERC2 from accessing to BRCA1 and ensuring BRCA1 stability. Inhibition of ASPM expression promotes HERC2-mediated BRCA1 degradation, compromises HR repair efficiency and chromosome stability, and sensitizes cancer cells to ionizing radiation. Moreover, we observed a synergistic effect between ASPM and PARP inhibition in killing cancer cells. This research has uncovered a novel function for ASPM in facilitating HR-mediated repair of DSBs by ensuring BRCA1 stability. ASPM might constitute a promising target for synthetic lethality-based cancer therapy.

SUBMITTER: Xu S

PROVIDER: S-EPMC8184511 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability.

Xu Shibin S Wu Xingxuan X Wang Peipei P Cao Sheng-Li SL Peng Bin B Xu Xingzhi X

iScience 20210512 6

DNA double-strand break (DSB) repair by homologous recombination (HR) is essential for ensuring genome stability. <i>Abnormal spindle-like microcephaly-associated</i> (<i>ASPM</i>) gene encodes a spindle protein that is commonly implicated in primary microcephaly. We found that ASPM is recruited to sites of DNA damage in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ligase HERC2, preventing HERC2 from accessing to BRCA1 and ensuring BRCA1 stability. Inhibition of ASPM expression ...[more]

PMID: 34142045

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