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

Shibin Xu,Xingxuan Wu,Peipei Wang,Sheng-Li Cao,Bin Peng,Xingzhi Xu

doi:10.1016/j.isci.2021.102534

Shibin Xu, Xingxuan Wu + Show 4 more

Open Access

https://doi.org/10.1016/j.isci.2021.102534

Copy DOI

Journal: iScience	Publication Date: May 12, 2021
Citations: 22	License type: cc-by

Affiliation: Capital Normal University, Shenzhen University

Abstract

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.

Highlights

Primary hereditary (MCPH) is a rare autosomal recessive genetic disease characterized by neurodevelopmental defects
We found that Abnormal spindle-like microcephalyassociated (ASPM) is recruited to sites of DNA damage in a PARP2-dependent manner
This research has uncovered a novel function for ASPM in facilitating homologous recombination (HR)-mediated repair of double-strand break (DSB) by ensuring BRCA1 stability

Summary

Introduction

Primary hereditary (MCPH) is a rare autosomal recessive genetic disease characterized by neurodevelopmental defects. MCPH can result from mutations in at least 25 genes, while mutations in the abnormal spindle-like microcephaly-associated (ASPM) gene (Bond et al, 2002) are the most common cause, representing ~40% of all MCPH cases (Jean et al, 2020). We are among the first to report that (1) both ASPM and microcephalin (MCPH1) are centrosomal/spindle proteins (Zhong et al, 2005, 2006); (2) both proteins functionally associate with breast cancer type 1 susceptibility protein BRCA1 (Xu et al, 2004; Zhong et al, 2005); (3) MCPH1 plays an important role in DNA damage-induced cellular responses (Xu et al, 2004). BRCA1 is one of 22 causative genes of Fanconi anemia (FA), a rare autosomal or x-chromosomal recessive human genetic disease (Fang et al, 2020). The FA pathway mediates interstrand crosslink repair via HR (Fang et al, 2020)

Methods

Results

Discussion

Conclusion