Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage

Successful recovery from DNA damage requires coordination of several biological processes. Eukaryotic cell cycle progression is delayed when the cells encounter DNA-damaging agents. This cell cycle delay allows the cells to cope with DNA damage by utilizing DNA repair enzymes. Thus, at least two processes, induction of the cell cycle delay and repair of damaged DNA, are coordinately required for recovery. In this study, a fission yeast rad mutant (slp1-362) was genetically investigated. In response to radiation, slp1 stops cell division; however, it does not restart it. This defect is suppressed when slp1-362 is combined with wee1-50 or cdc2-3w; in these mutants, the onset of mitosis is advanced due to the premature activation of p34cdc2. In contrast, slp1 is synthetically lethal with cdc25, nim1/cdr1, or cdr2, all of which are unable to activate the p34cdc2 kinase correctly. These genetic interactions of slp1 with cdc2 and its modulators imply that slp1 is not defective in either "induction of cell cycle delay" or "DNA repair." slp1+ may be involved in a critical process which restarts cell cycle progression after the completion of DNA repair. Molecular cloning of slp1+ revealed that slp1+ encodes a putative 488-amino-acid polypeptide exhibiting significant homology to WD-domain proteins, namely, CDC20 (budding yeast), p55CDC (human), and Fizzy (fly). A possible role of slp1+ is proposed.

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Faculty Opinions recommendation of E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005538.71460 ◽

2002 ◽

Author(s):

Michael Meisterernst

Keyword(s):

Cell Cycle ◽

Dna Repair ◽

Cell Cycle Progression ◽

Cycle Progression

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Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

Journal of Bacteriology ◽

10.1128/jb.00408-19 ◽

2019 ◽

Vol 202 (2) ◽

Cited By ~ 5

Author(s):

Peter E. Burby ◽

Lyle A. Simmons

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Division ◽

Dna Replication ◽

Cell Cycle Progression ◽

Genome Instability ◽

Sos Response ◽

Bacterial Cells ◽

Cycle Progression ◽

Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

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STAU2 protein level is controlled by caspases and the CHK1 pathway and regulates cell cycle progression in the non-transformed hTERT-RPE1 cells

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00352-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lionel Condé ◽

Yulemi Gonzalez Quesada ◽

Florence Bonnet-Magnaval ◽

Rémy Beaujois ◽

Luc DesGroseillers

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Proliferation ◽

Dna Damage ◽

Steady State ◽

Posttranscriptional Regulation ◽

Cell Cycle Progression ◽

Rna Binding ◽

Regulation Of Gene Expression ◽

Cycle Progression

AbstractBackgroundStaufen2 (STAU2) is an RNA binding protein involved in the posttranscriptional regulation of gene expression. In neurons, STAU2 is required to maintain the balance between differentiation and proliferation of neural stem cells through asymmetric cell division. However, the importance of controlling STAU2 expression for cell cycle progression is not clear in non-neuronal dividing cells. We recently showed that STAU2 transcription is inhibited in response to DNA-damage due to E2F1 displacement from theSTAU2gene promoter. We now study the regulation of STAU2 steady-state levels in unstressed cells and its consequence for cell proliferation.ResultsCRISPR/Cas9-mediated and RNAi-dependent STAU2 depletion in the non-transformed hTERT-RPE1 cells both facilitate cell proliferation suggesting that STAU2 expression influences pathway(s) linked to cell cycle controls. Such effects are not observed in the CRISPR STAU2-KO cancer HCT116 cells nor in the STAU2-RNAi-depleted HeLa cells. Interestingly, a physiological decrease in the steady-state level of STAU2 is controlled by caspases. This effect of peptidases is counterbalanced by the activity of the CHK1 pathway suggesting that STAU2 partial degradation/stabilization fines tune cell cycle progression in unstressed cells. A large-scale proteomic analysis using STAU2/biotinylase fusion protein identifies known STAU2 interactors involved in RNA translation, localization, splicing, or decay confirming the role of STAU2 in the posttranscriptional regulation of gene expression. In addition, several proteins found in the nucleolus, including proteins of the ribosome biogenesis pathway and of the DNA damage response, are found in close proximity to STAU2. Strikingly, many of these proteins are linked to the kinase CHK1 pathway, reinforcing the link between STAU2 functions and the CHK1 pathway. Indeed, inhibition of the CHK1 pathway for 4 h dissociates STAU2 from proteins involved in translation and RNA metabolism.ConclusionsThese results indicate that STAU2 is involved in pathway(s) that control(s) cell proliferation, likely via mechanisms of posttranscriptional regulation, ribonucleoprotein complex assembly, genome integrity and/or checkpoint controls. The mechanism by which STAU2 regulates cell growth likely involves caspases and the kinase CHK1 pathway.

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Regulation of DNA-damage responses and cell-cycle progression by the chromatin remodelling factor CHD4

The EMBO Journal ◽

10.1038/emboj.2010.188 ◽

2010 ◽

Vol 29 (18) ◽

pp. 3130-3139 ◽

Cited By ~ 220

Author(s):

Sophie E Polo ◽

Abderrahmane Kaidi ◽

Linda Baskcomb ◽

Yaron Galanty ◽

Stephen P Jackson

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Chromatin Remodelling ◽

Cycle Progression ◽

Dna Damage Responses

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Human POLD1 modulates cell cycle progression and DNA damage repair

BMC Biochemistry ◽

10.1186/s12858-015-0044-7 ◽

2015 ◽

Vol 16 (1) ◽

Cited By ~ 16

Author(s):

Jing Song ◽

Ping Hong ◽

Chengeng Liu ◽

Yueqi Zhang ◽

Jinling Wang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Progression ◽

Dna Damage Repair ◽

Cycle Progression ◽

Damage Repair

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The tail that wags the dog: p12, the smallest subunit of DNA polymerase δ, is degraded by ubiquitin ligases in response to DNA damage and during cell cycle progression

Cell Cycle ◽

10.4161/cc.27407 ◽

2013 ◽

Vol 13 (1) ◽

pp. 23-31 ◽

Cited By ~ 22

Author(s):

Marietta Y.W.T. Lee ◽

Sufang Zhang ◽

Szu Hua Lin ◽

Xiaoxiao Wang ◽

Zbigniew Darzynkiewicz ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Dna Polymerase ◽

Cell Cycle Progression ◽

Ubiquitin Ligases ◽

Cycle Progression ◽

Dna Polymerase Δ

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DNA damage inhibits proteolysis of the B-type cyclin Clb5 in S. cerevisiae

Journal of Cell Science ◽

10.1242/jcs.110.15.1813 ◽

1997 ◽

Vol 110 (15) ◽

pp. 1813-1820

Author(s):

D. Germain ◽

J. Hendley ◽

B. Futcher

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Tyrosine Phosphorylation ◽

Cell Cycle Progression ◽

Cycle Phase ◽

Cycle Progression ◽

Ubiquitin Pathway ◽

Cyclin Dependent Kinases ◽

Transition Points ◽

Checkpoint Genes

Cell cycle progression is mediated by waves of specific cyclin dependent kinases (CDKs) in all eukaryotes. Cyclins are degraded by the ubiquitin pathway of proteolysis. The recent identification of several components of the cyclin proteolysis machinery has highlighted both the importance of proteolysis at multiple transition points in the cell cycle and the involvement of other substrates degraded by the same machinery. In this study, we have investigated the effects of DNA damage on the cyclin proteolytic machinery in Saccharomyces cerevisiae. We find that the half-life of the B-type cyclin Clb5 is markedly increased following DNA damage while that of G1 cyclins is not. This effect is independent of cell cycle phase. Clb5 turnover requires p34CDC28 activity. Stabilisation of Clb5 correlates with an increase in tyrosine phosphorylation of p34CDC28, but stabilisation does not require this tyrosine phosphorylation. The stabilisation is independent of the checkpoint genes Mec1 and Rad53. These observations establish a new link between the regulation of proteolysis and DNA damage.

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