cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
10.1007/s13238-021-00879-y
- Author:
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
2
;
Yong ZHAO
1
Author Information
1. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
2. MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510006, China. liuhy5@mail.sysu.edu.cn.
- Publication Type:Research Support, Non-U.S. Gov't
- Keywords:
DNA damage response;
cGAS;
chromosome end-to-end fusion;
genome stability;
mitosis;
non-homologous end joining;
telomeres
- From:
Protein & Cell
2022;13(1):47-64
- CountryChina
- Language:English
-
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.
