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주윤기Yoon Ki Joo
Yale University
Mol. Cell, Oct 19 2023, 83 (20) S1097-2765(23)00698-6 | https://doi.org/10.1016/j.molcel.2023.09.003
ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei
Yoon Ki Joo 1,2, Elizabeth M. Black 1,2, Isabelle Trier 1,2, Wisse Haakma 3, Lee Zou 3,4,5,6, Lilian Kabeche 1,2
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA
2Yale Cancer Biology Institute, Yale University, New Haven, CT 06516, USA
3Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Boston, MA 02129, USA
4Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
5Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27708, USA
6Lead contact
Corresponding authors: Lee Zou, Lilian Kabeche
Abstract
The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms.
논문정보
- Research article
- 2023년 10월 (BRIC 등록일 2023-12-21)
- 국외 연구진
- 생명과학 > 세포생물학
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