Checkpoint recovery after DNA damage: a rolling stop for CDKs

Duursma, Anja; Cimprich, Karlene A.

doi:10.1038/embor.2010.76

Cited by 4 publications

(4 citation statements)

References 11 publications

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“…This idea is in line with a recent report (29) revealing that cyclin A-CDK activity has to be maintained to a certain level during the establishment of the checkpoint to allow the activation of FoxM1, a transcription factor whose activity is critical for the recovery (30). Our findings suggest a model in which DN-CDC25B would be dedicated variants of CDC25B that would keep the cyclin A-CDK activity above a critical threshold required for the resumption of the cell-cycle.…”

Section: Discussionsupporting

confidence: 78%

Identification of N-Terminally Truncated Stable Nuclear Isoforms of CDC25B That Are Specifically Involved in G2/M Checkpoint Recovery

Jullien

Bugler²,

Dozier³

et al. 2011

Cancer Research

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CDC25B phosphatases must activate cyclin B-CDK1 complexes to restart the cell cycle after an arrest in G2 phase caused by DNA damage. However, little is known about the precise mechanisms involved in this process, which may exert considerable impact on cancer susceptibility and therapeutic responses. Here we report the discovery of novel N-terminally truncated CDC25B isoforms, referred to as DN-CDC25B, with an exclusively nuclear and nonredundant function in cell cycle re-initiation after DNA damage. DN-CDC25B isoforms are expressed from a distinct promoter not involved in expression of canonical full-length isoforms. Remarkably, in contrast to the high lability and spatial dynamism of the full-length isoforms, DN-CDC25B isoforms are highly stable and exclusively nuclear, strongly suggesting the existence of two pools of CDC25B phosphatases in the cell that have functionally distinct properties. Using isoform-specific siRNA, we found that depleting full-length isoforms, but not DN-CDC25B isoforms, delays entry into mitosis. Thus, in an unperturbed cell cycle, the fulllength isoforms are exclusively responsible for activating cyclin B-CDK1. Strikingly, in the late response to DNA damage, we found a CHK1-dependent shift in accumulation of CDC25B isoforms toward the DN-CDC25B species. Under this physiological stress condition, the DN-CDC25B isoform was found to play a crucial, nonredundant function in restarting the cell cycle after DNA damage-induced G2 phase arrest. Our findings reveal the existence of a previously unrecognized CDC25B isoform that operates specifically in the nucleus to reinitiate G2/M transition after DNA damage. Cancer Res; 71(5); 1968-77. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 78%

Identification of N-Terminally Truncated Stable Nuclear Isoforms of CDC25B That Are Specifically Involved in G2/M Checkpoint Recovery

Jullien

Bugler²,

Dozier³

et al. 2011

Cancer Research

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“…Control of cell cycle dynamics is a likely mechanism by which nutrient status affects proliferation. Cells exit the cell cycle for a variety of reasons, including G0 cell cycle exit for differentiation, or irreversible G2 arrest in response to DNA damage (Barnum and O'Connell, 2014;DiPaola, 2002;Duursma and Cimprich, 2010) or viral infection (Bressy et al, 2019;Davy and Doorbar, 2007). Dividing cells typically pause for some period in G0, pending signals that regulate progression into G1 and subsequent cell division or terminal differentiation.…”

Section: Introductionmentioning

confidence: 99%

Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors

McKeown

Cline

2019

Development

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In the Materials and Methods section, the concentration of rapamycin used was incorrect. Corrected: mTOR was blocked with a bath solution containing 10 µM rapamycin (Sigma-Aldrich) diluted in rearing media for up to 48 h. Original: mTOR was blocked with a bath solution containing 10 mM rapamycin (Sigma-Aldrich) diluted in rearing media for up to 48 h. Both the online full-text and PDF versions have been updated.

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“…First, we measured their effect on checkpoint recovery competence in cells depleted for p53. Whereas transformed cells like U2OS maintain the competence to recover, primary RPE1 cells lose this ability rather quickly, which makes RPE1 the more representative cell model to study this cell fate-determining response [36,37]. While studying the recovery competence after co-depletion of p53 in RPE1 cells, we found that similar to the PPM1D-positive control, depletion of PHF3, RBBP6, RAD54L, KAT5, SMC3, PHF6, LIN9, TAF12, SMC1, NIPBL, ACTL6A, TRRAP, and RAD21 affected recovery in a p53dependent manner, indicating the involvement of these genes in the regulation of DNA damage-induced p53 activation ( Fig 2B).…”

mentioning

confidence: 99%

PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

et al. 2019

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The cellular response to DNA breaks is influenced by chromatin compaction. To identify chromatin regulators involved in the DNA damage response, we screened for genes that affect recovery following DNA damage using an RNAi library of chromatin regulators. We identified genes involved in chromatin remodeling, sister chromatid cohesion, and histone acetylation not previously associated with checkpoint recovery. Among these is the PHD finger protein 6 (PHF6), a gene mutated in Börjeson-Forssman-Lehmann syndrome and leukemic cancers. We find that loss of PHF6 dramatically compromises checkpoint recovery in G2 phase cells. Moreover, PHF6 is rapidly recruited to sites of DNA lesions in a PARPdependent manner and required for efficient DNA repair through classical non-homologous end joining. These results indicate that PHF6 is a novel DNA damage response regulator that promotes end joining-mediated repair, thereby stimulating timely recovery from the G2 checkpoint.

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Checkpoint recovery after DNA damage: a rolling stop for CDKs

Cited by 4 publications

References 11 publications

Identification of N-Terminally Truncated Stable Nuclear Isoforms of CDC25B That Are Specifically Involved in G2/M Checkpoint Recovery

Identification of N-Terminally Truncated Stable Nuclear Isoforms of CDC25B That Are Specifically Involved in G2/M Checkpoint Recovery

Nutrient restriction causes reversible G2 arrest in Xenopus neural progenitors

PHF6 promotes non‐homologous end joining and G2 checkpoint recovery

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