期刊
NATURE CELL BIOLOGY
卷 23, 期 8, 页码 894-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41556-021-00723-9
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资金
- National Natural Science Foundation of China [32090032, 32070713, 82002985, 81872298, 81802754]
- Mayo foundation
ASTE1, as a downstream effector of the shieldin complex, cleaves single-stranded and 3' overhang DNA to promote shieldin-dependent non-homologous end-joining, leading to impaired DSB repair and resistance to PARP inhibitors in BRCA1-deficient cells.
The shieldin complex functions as the downstream effector of 53BP1-RIF1 to promote DNA double-strand break end-joining by restricting end resection. The SHLD2 subunit binds to single-stranded DNA ends and blocks end resection through OB-fold domains. Besides blocking end resection, it is unclear how the shieldin complex processes SHLD2-bound single-stranded DNA and promotes non-homologous end-joining. Here, we identify a downstream effector of the shieldin complex, ASTE1, as a structure-specific DNA endonuclease that specifically cleaves single-stranded DNA and 3 ' overhang DNA. ASTE1 localizes to DNA damage sites in a shieldin-dependent manner. Loss of ASTE1 impairs non-homologous end-joining, leads to hyper-resection and causes defective immunoglobulin class switch recombination. ASTE1 deficiency also causes resistance to poly(ADP-ribose) polymerase inhibitors in BRCA1-deficient cells owing to restoration of homologous recombination. These findings suggest that ASTE1-mediated 3 ' single-stranded DNA end cleavage contributes to the control of DSB repair choice by 53BP1, RIF1 and shieldin. Zhao et al. show that ASTE1 is a downstream effector of the shieldin complex, which cleaves the 3 ' overhang of DNA double-strand breaks to promote shieldin-dependent non-homologous end-joining.
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