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

Fei Zhao, Wootae Kim, Huanyao Gao, Chao Liu, Yong Zhang, Yuping Chen, Min Deng, Qin Zhou, Jinzhou Huang, Qi Hu, Shih Hsun Chen, Somaira Nowsheen, Jake A. Kloeber, Bo Qin, Ping Yin, Xinyi Tu, Guijie Guo, Sisi Qin, Chao Zhang, Ming GaoKuntian Luo, Yilun Liu, Zhenkun Lou, Jian Yuan

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)894-904
Number of pages11
JournalNature Cell Biology
Issue number8
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Cell Biology


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