摘要：SummaryDNA 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.Graphical abstractDisplay OmittedHighlights•ASPM is recruited to sites of DNA damage in a PARP2-dependent manner.•ASPM promotes DSB-end resection to facilitate HR repair.•ASPM prevents HERC2 from accessing to BRCA1 and ensuring BRCA1 stability.•Inhibition of ASPM sensitizes cancer cells to ionizing radiation and PARP inhibitor.Molecular biology; Cell biology; Functional aspects of cell biology
