ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection

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.

Automated summary

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.