生物
基因组不稳定性
细胞生物学
DNA损伤
雷达51
拉明
微核试验
胞质分裂
变色
磷酸化
DNA
细胞
分子生物学
遗传学
核心
细胞分裂
化学
有机化学
毒性
作者
Yoon Ki Joo,Elizabeth M. Black,Isabelle Trier,Wisse E. Haakma,Lee Zou,Lilian Kabeche
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-10-01
卷期号:83 (20): 3642-3658.e4
被引量:5
标识
DOI:10.1016/j.molcel.2023.09.003
摘要
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.
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