RESEARCH ARTICLE

cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence

  • Xiaocui Li 1 ,
  • Xiaojuan Li 1 ,
  • Chen Xie 1 ,
  • Sihui Cai 1 ,
  • Mengqiu Li 1 ,
  • Heping Jin 1 ,
  • Shu Wu 1 ,
  • Jun Cui 1 ,
  • Haiying Liu , 1,3 ,
  • Yong Zhao 1,2
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  • 1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yatsen University, Guangzhou 510006, China
  • 2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510006, China
  • 3. Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China

Received date: 19 May 2021

Accepted date: 06 Sep 2021

Published date: 15 Jan 2022

Copyright

2021 The Author(s)

Abstract

As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/ TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

Cite this article

Xiaocui Li , Xiaojuan Li , Chen Xie , Sihui Cai , Mengqiu Li , Heping Jin , Shu Wu , Jun Cui , Haiying Liu , Yong Zhao . cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence[J]. Protein & Cell, 2022 , 13(1) : 47 -64 . DOI: 10.1007/s13238-021-00879-y

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