Replication Stress Induces ATR/CHK1-Dependent Nonrandom Segregation of Damaged Chromosomes

Meichun Xing; Fengjiao Zhang; Hongwei Liao; Sisi Chen; Luanqing Che; Xiaohui Wang; Zhengqiang Bao; Fang Ji; Gaoying Chen; Huihui Zhang; Wen Li; Zhihua Chen; Ying Liu; Ian D Hickson; Huahao Shen; Songmin Ying

doi:10.1016/j.molcel.2020.04.005

Replication Stress Induces ATR/CHK1-Dependent Nonrandom Segregation of Damaged Chromosomes

Mol Cell. 2020 May 21;78(4):714-724.e5. doi: 10.1016/j.molcel.2020.04.005. Epub 2020 Apr 29.

Authors

Meichun Xing¹, Fengjiao Zhang¹, Hongwei Liao¹, Sisi Chen¹, Luanqing Che², Xiaohui Wang¹, Zhengqiang Bao¹, Fang Ji¹, Gaoying Chen¹, Huihui Zhang¹, Wen Li², Zhihua Chen², Ying Liu³, Ian D Hickson⁴, Huahao Shen⁵, Songmin Ying⁶

Affiliations

¹ Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou 310009, China.
² Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
³ Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
⁴ Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address: [email protected].
⁵ Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; State Key Laboratory of Respiratory Diseases, Guangzhou, Guangdong 510120, China. Electronic address: [email protected].
⁶ Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou 310009, China. Electronic address: [email protected].

PMID: 32353258
DOI: 10.1016/j.molcel.2020.04.005

Abstract

Nonrandom DNA segregation (NDS) is a mitotic event in which sister chromatids carrying the oldest DNA strands are inherited exclusively by one of the two daughter cells. Although this phenomenon has been observed across various organisms, the mechanism and physiological relevance of this event remain poorly defined. Here, we demonstrate that DNA replication stress can trigger NDS in human cells. This biased inheritance of old template DNA is associated with the asymmetric DNA damage response (DDR), which derives at least in part from telomeric DNA. Mechanistically, we reveal that the ATR/CHK1 signaling pathway plays an essential role in mediating NDS. We show that this biased segregation process leads to cell-cycle arrest and cell death in damaged daughter cells inheriting newly replicated DNA. These data therefore identify a key role for NDS in the maintenance of genomic integrity within cancer cell populations undergoing replication stress due to oncogene activation.

Keywords: ATR/CHK1; asymmetric DNA damage response; biased inheritance; nonrandom DNA segregation; replication stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins / genetics
Ataxia Telangiectasia Mutated Proteins / metabolism*
Checkpoint Kinase 1 / genetics
Checkpoint Kinase 1 / metabolism*
Chromosome Segregation
Chromosomes, Human / genetics*
DNA Damage*
DNA Replication*
HeLa Cells
Humans
Mitosis*
Signal Transduction

Substances

ATM protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
CHEK1 protein, human
Checkpoint Kinase 1