Chk1 dynamics in G2 phase upon replication stress predict daughter cell outcome

Lebrec, Vicente; Poteau, Marion; Morretton, Jean-Philippe; Gavet, Olivier

doi:10.1016/j.devcel.2022.02.013

Cited by 18 publications

(20 citation statements)

References 85 publications

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“…These results are in line with a recent report that shows that CDC7 activity is required for CHK1 activation during unperturbed S phase 46 and suggest that the accumulation of POLA/PRIM on chromatin after origin firing leads to the activation of ATR. ATR activation is a two-step process mediated by the recruitment of the ATR-ATRIP complex to ssDNA by RPA and its activation through specific domains in TOPBP1 or ETAA1.…”

Section: Vcp/p97 Extracts Pola/prim From Chromatinsupporting

confidence: 93%

The activation of ATR during unperturbed DNA replication is restricted by VCP/p97 through the extraction of DNA polymerase α/Primase from chromatin

Rodríguez‐Acebes

Martín-Rufo

Fernández-Llorente

et al. 2022

Preprint

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The replication stress response is an essential pathway that deals with the lesions that halt the progression of DNA replication forks even during an unperturbed S phase. Basal activation of the ATR and CHK1 kinases prevents the premature firing of origins of replication during S phase, avoiding the activation of an excessive number of replication forks and the appearance of genomic instability. However, the mechanisms that regulate ATR activation in the unperturbed S phase have not been fully determined. Here we present evidence showing that the AAA ATPase VCP/p97 regulates the presence of the DNA polymerase α/Primase complex (POLA/PRIM) on chromatin after origin firing, thus limiting the generation of primed DNA structures that mediate the activation of ATR by TOPBP1. As a consequence, inhibiting VCP/p97 activates ATR and CHK1 leading to cell cycle arrest in G2/M. We propose that the loading of POLA/PRIM after origin firing drives the basal activation of ATR during an unperturbed S phase and VCP/p97 regulates this activation through the extraction of POLA/PRIM from chromatin.

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Section: Vcp/p97 Extracts Pola/prim From Chromatinsupporting

confidence: 93%

The activation of ATR during unperturbed DNA replication is restricted by VCP/p97 through the extraction of DNA polymerase α/Primase from chromatin

Rodríguez‐Acebes

Martín-Rufo

Fernández-Llorente

et al. 2022

Preprint

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“…In somatic cells, CHK1 kinase prevents mitotic entry until DNA replication is completed (Kalogeropoulos et al, 2004; Lebrec et al, 2022; Saldivar et al, 2018; Zachos et al, 2005). CHK1 kinase also regulates S phase progression, including replication origin firing, replication fork speed progression, and DNA damage response in S phase (Dandoulaki et al, 2018; Michelena et al, 2019; Niida et al, 2005; Syljuåsen et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…This finding is consistent with other studies (Branigan et al, 2021;Lam et al, 2004), where Chk1 depletion or inhibition causes premature mitosis in cells with only mildly, but not severely, under-replicated DNA. CHK1 is activated after replication stress in somatic cells and early embryos (González Besteiro & Gottifredi 2015;Lam et al, 2004;Lebrec et al, 2022;Lemmens et al, 2018;Michelena et al, 2019;Moiseeva et al, 2019;Muralidharan et al, 2020;Palmerola et al, 2022;Syljuåsen et al, 2005;Zachos et al, 2005). Replication stress signalling is usually orchestrated by ATR kinase (Eykelenboom et al, 2013;Saldivar et al, 2018).…”

Section: The Long G2 Phase In 2-cell Embryos Is Necessary For Genome ...mentioning

confidence: 99%

“…ATR and CHK1 are DDR kinases that regulate cell cycle progression by maintaining replication checkpoint signaling (Eykelenboom et al, 2013; Kalogeropoulos et al, 2004; Lebrec et al, 2022; Saldivar et al, 2018; Zachos et al, 2005). The replication checkpoint prevents mitosis before DNA replication is finished (Enoch & Nurse 1990; Hartwell & Weinert 1989).…”

Section: Introductionmentioning

confidence: 99%

“…It should be noted that incompletely replicated DNA caused by replication stress during human embryonic development is a major cause of an increased incidence of aneuploidy in human embryos (Palmerola et al, 2022). ATR and CHK1 are DDR kinases that regulate cell cycle progression by maintaining replication checkpoint signaling (Eykelenboom et al, 2013;Kalogeropoulos et al, 2004;Lebrec et al, 2022;Saldivar et al, 2018;Zachos et al, 2005). The replication checkpoint prevents mitosis before DNA replication is finished (Enoch & Nurse 1990;Hartwell & Weinert 1989).…”

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confidence: 99%

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CHK1-CDC25A-CDK1 regulate cell cycle progression in early mouse embryos to protect genome integrity

Knoblochová

Duricek

Vaškovičová

et al. 2022

Preprint

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After fertilization, remodeling of the oocyte and sperm genomes is essential to convert these highly differentiated non-dividing transcriptionally quiescent cells into early cleavage-stage transcriptionally active totipotent blastomeres. This developmental transition is accompanied by cell cycle adaptation such as lengthening or shortening of the gap phases G1 and G2. However, regulation of these cell cycle changes is poorly understood, especially in mammals. Checkpoint kinase 1 (CHK1) is a protein kinase that regulates cell cycle progression in somatic cells. Here, we show that CHK1 regulates cell cycle progression in early mouse embryos by restraining CDK1 kinase activity due to CDC25A phosphatase degradation. CHK1 kinase also ensures the long G2 phase needed for genome activation and reprogramming gene expression in 2-cell stage mouse embryos. Last,Chk1depletion leads to DNA damage and chromosome segregation errors that result in aneuploidy and infertility.

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Monitoring Chk1 kinase activity dynamics in live single cell imaging assays

Lebrec

Gavet

2024

Methods in Cell Biology

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Chk1 dynamics in G2 phase upon replication stress predict daughter cell outcome

Cited by 18 publications

References 85 publications

The activation of ATR during unperturbed DNA replication is restricted by VCP/p97 through the extraction of DNA polymerase α/Primase from chromatin

The activation of ATR during unperturbed DNA replication is restricted by VCP/p97 through the extraction of DNA polymerase α/Primase from chromatin

CHK1-CDC25A-CDK1 regulate cell cycle progression in early mouse embryos to protect genome integrity

Monitoring Chk1 kinase activity dynamics in live single cell imaging assays

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