ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability
Shibin Xu,
Xingxuan Wu,
Peipei Wang,
Sheng-Li Cao,
Bin Peng,
Xingzhi Xu
Affiliations
Shibin Xu
College of Life Sciences, Capital Normal University, Beijing 100048, China; Department of Chemistry, Capital Normal University, Beijing 100048, China; Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
Xingxuan Wu
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
Peipei Wang
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; International Cancer Center, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China
Sheng-Li Cao
Department of Chemistry, Capital Normal University, Beijing 100048, China; Corresponding author
Bin Peng
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; International Cancer Center, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; Corresponding author
Xingzhi Xu
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; Shenzhen University-Friedrich Schiller Universität Jena Joint PhD Program in Biomedical Sciences, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; International Cancer Center, Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China; Corresponding author
Summary: 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.
