期刊
DEVELOPMENTAL CELL
卷 57, 期 5, 页码 638-+出版社
CELL PRESS
DOI: 10.1016/j.devcel.2022.02.013
关键词
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资金
- Agence Nationale de la Recherche [ANR-17-CE13-0011-03]
- IDI 2016project - IDEX Paris-Saclay [ANR-11-IDEX-0003-02]
- Ligue Nationale Contre le Cancer [IP/SC-15956]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE13-0011] Funding Source: Agence Nationale de la Recherche (ANR)
Researchers decoded how the DNA replication checkpoint (DRC) allows cells to enter mitosis after replication stress (RS) by developing a FRET-based Chk1 activity sensor. They found that Chk1 activity is sustained during S phase through replication origin firing and is reactivated upon RS to prevent premature mitosis.
In human cells, ATR/Chk1 signaling couples S phase exit with the expression of mitotic inducers and prevents premature mitosis upon replication stress (RS). Nonetheless, under-replicated DNA can persist at mitosis, prompting chromosomal instability. To decipher how the DNA replication checkpoint (DRC) allows cells to enter mitosis over time upon RS, we developed a FRET-based Chk1 activity sensor. During unperturbed growth, a basal Chk1 activity level is sustained throughout S phase and relies on replication origin firing. Incremental RS triggers stepwise Chk1 over-activation that delays S-phase, suggesting a rheostat like role for DRC coupled with the replication machinery. Upon RS, Chk1 is inactivated as DNA replication terminates but surprisingly is reactivated in a subset of G2 cells, which relies on Cdk1/2 and Plk1 and prevents mitotic entry. Cells can override active Chk1 signaling and reach mitosis onset, revealing checkpoint adaptation. Cell division following Chk1 reactivation in G2 results in a p53/p21-dependent G1 arrest, eliminating the daughter cells from proliferation.
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