Inherited DNA lesions determine G1 duration in the next cell cycle

Lezaja, Aleksandra; Altmeyer, Matthias

doi:10.1080/15384101.2017.1383578

Cited by 64 publications

(51 citation statements)

References 43 publications

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“…2). p53BP1 bodies have been implicated as one of the contributors to the G 1 -S checkpoint activation by p53 WT cells (38). However, to our knowledge, virtually no evidence (with one exception; ref.…”

Section: Discussionmentioning

confidence: 94%

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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The p53 gene is the most commonly mutated gene in solid tumors, but leveraging p53 status in therapy remains a challenge. Previously, we determined that p53 deficiency sensitizes head and neck cancer cells to AZD1775, a WEE1 kinase inhibitor, and translated our findings into a phase I clinical trial. Here, we investigate how p53 affects cellular responses to AZD1775 at the molecular level. We found that p53 modulates both replication stress and mitotic deregulation triggered by WEE1 inhibition. Without p53, slowing of replication forks due to replication stress is exacerbated. Abnormal, gH2AX-positive mitoses become more common and can proceed with damaged or underreplicated DNA. p53-deficient cells fail to properly recover from WEE1 inhibition and exhibit fewer 53BP1 nuclear bodies despite evidence of unresolved damage. A faulty G 1 -S checkpoint propagates this damage into the next division. Together, these deficiencies can intensify damages in each consecutive cell cycle in the drug. Implications:The data encourage the use of AZD1775 in combination with genotoxic modalities against p53-deficient head and neck squamous cell carcinoma. Results Cell-cycle progression and DNA-damage/replication stress response in WEE1 inhibitor-treated HNSCC cellsPhenotypes elicited by a therapeutically relevant dose of the WEE1 inhibitor AZD1775 were first demonstrated in the TP53 Diab et al.

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Section: Discussionmentioning

confidence: 94%

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Diab

Kao

Kehrli

et al. 2019

Molecular Cancer Research

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“…Our results suggest persistent DNA damage could provide the signal that leads to the observed descendant cell death. However if so, the lack of cell cycle arrest we report in intermediate generations raises the interesting possibility that inherited DNA damage does not cause the canonical cell cycle checkpoint response perhaps via a yet to be identified checkpoint marking or memory process analogous to those demonstrated for replication stress [23][24][25] .…”

Section: Discussionmentioning

confidence: 79%

Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage

Esposito

2018

Preprint

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DNA damage in proliferating mammalian cells causes death 1 , senescence 2 or continued survival, via checkpoints that monitor damage and regulate cell cycle progression, DNA repair and fate determination 3 . Cell cycle checkpoints facilitate tumour suppression by preventing the generation of proliferating mutated cells 4 , particularly by blocking passage of DNA lesions into replication and mitosis 5 . While checkpoint non-fidelity permits cells to carry genomic aberrations into subsequent cell cycle phases 6 , its long-term consequences on lineages descendant from damaged cells remains poorly characterised. Devising methods for microscopy-based lineage tracing, we unexpectedly demonstrate that transient DNA damage to single living cells bearing a negligent checkpoint induces heterogenous cell-fate outcomes in their descendant generations removed from the initial insult. After transiently damaged cells undergo an initial arrest, pairs of descendant cells without obvious cell-cycle abnormalities either divide or die in a seemingly stochastic way. Progeny of transiently damaged cells may die generations afterwards, creating considerable variability of lineage fitness that promotes overall persistence in a mutagenic environment. Descendants of damaged cells frequently form micronuclei, activating immunogenic signalling. Our findings reveal previously unrecognized, heterogenous effects of cellular DNA damage that manifest long afterwards in descendant cells. We suggest that these heterogenous descendant cell-fate responses may function physiologically to ensure the elimination and immune clearance of damaged cell lineages, but pathologically, may enable the prolonged survival of cells bearing mutagenic damage.

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“…This is perhaps expected, as exit from G1 is a major restriction point before DNA synthesis and the level of numerous proteins, including known oncogenes, regulate this decision. Molecular changes that would eliminate the usual controls that govern the decision to divide include deregulated c-Myc, Cyclin D/E, and p53, and these genes are found mutated in up to 90% of B lymphomas [33–41]. It is also likely that the removal of limiting steps in cell cycle progression by deregulating the production of regulatory proteins can explain the reduced correlations in times for G1 and S/G2/M in individual lymphoma cells compared to primary B cells.…”

Section: Discussionmentioning

confidence: 99%

Converse Smith-Martin cell cycle kinetics by transformed B lymphocytes

et al. 2018

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Recent studies using direct live cell imaging have reported that individual B lymphocytes have correlated transit times between their G1 and S/G2/M phases. This finding is in contradiction with the influential model of Smith and Martin that assumed the bulk of the total cell cycle time variation arises in the G1 phase of the cell cycle with little contributed by the S/G2/M phase. Here we extend these studies to examine the relation between cell cycle phase lengths in two B lymphoma cell lines. We report that transformed B lymphoma cells undergo a short G1 period that displays little correlation with the time taken for the subsequent S/G2/M phase. Consequently, the bulk of the variation noted for total division times within a population is found in the S/G2/M phases and not the G1 phase. Models that reverse the expected source of variation and assume a single deterministic time in G1 followed by a lag + exponential distribution for S/G2/M fit the data well. These models can be improved further by adopting two sequential distributions or by using the stretched lognormal model developed for primary lymphocytes. We propose that shortening of G1 transit times and uncoupling from other cell cycle phases may be a hallmark of lymphocyte transformation that could serve as an observable phenotypic marker of cancer evolution.

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Inherited DNA lesions determine G1 duration in the next cell cycle

Cited by 64 publications

References 43 publications

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Multiple Defects Sensitize p53-Deficient Head and Neck Cancer Cells to the WEE1 Kinase Inhibition

Checkpoint non-fidelity induces a complex landscape of lineage fitness after DNA damage

Converse Smith-Martin cell cycle kinetics by transformed B lymphocytes

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