scholarly journals Rescue of DNA damage in cells after constricted migration reveals bimodal mechano-regulation of cell cycle

2018 ◽  
Author(s):  
Yuntao Xia ◽  
Charlotte R Pfeifer ◽  
Kuangzheng Zhu ◽  
Jerome Irianto ◽  
Dazhen Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genomic Variation ◽  
Chromatin Binding ◽  
Cell Cycle Delay ◽  
Repair Factor ◽  
Regulation Of Cell Cycle ◽  
Break Formation ◽  
Damage Marker ◽  
Partial Effects

Migration through constrictions can clearly rupture nuclei and mis-localize nuclear proteins but damage to DNA remains uncertain as does any effect on cell cycle. Here, myosin-II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent delay in cell cycle is unaffected. Co-overexpression of multiple DNA repair factors and antioxidant inhibition of break formation also have partial effects, independent of rupture. Complete rescue of both DNA damage and cell cycle delay by myosin inhibition plus antioxidant reveals a bimodal dependence of cell cycle on DNA damage. Migration through custom-etched pores yields the same bimodal, with ~4-um pores causing intermediate levels of damage and cell cycle delay. Micronuclei (generated in faulty division) of the smallest diameter appear similar to ruptured nuclei, with high DNA damage and entry of chromatin-binding cGAS (cyclic-GMP-AMP-synthase) from cytoplasm but low repair factor levels. Increased genomic variation after constricted migration is quantified in expanding clones and is consistent with (mis)repair of excess DNA damage and subsequent proliferation.

scholarly journals Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle

2019 ◽  
Vol 218 (8) ◽  
pp. 2545-2563 ◽  
Author(s):  
Yuntao Xia ◽  
Charlotte R. Pfeifer ◽  
Kuangzheng Zhu ◽  
Jerome Irianto ◽  
Dazhen Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Damage Threshold ◽  
Chromatin Binding ◽  
Lamin B ◽  
Cell Cycle Block ◽  
Break Formation ◽  
Damage Marker ◽  
Partial Effects ◽  
Nuclear Rupture

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation.

scholarly journals The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Eutteum Jeong ◽  
Owen A Brady ◽  
José A Martina ◽  
Mehdi Pirooznia ◽  
Ilker Tunc ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcription Factors ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Double Knockout ◽  
Protein Levels ◽  
Regulation Of Cell Cycle

The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.

scholarly journals ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response

2020 ◽  
Vol 1867 (8) ◽  
pp. 118716 ◽  
Author(s):  
Eduardo A. Sagredo ◽  
Alfredo I. Sagredo ◽  
Alejandro Blanco ◽  
Pamela Rojas De Santiago ◽  
Solange Rivas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Damage Response ◽  
Regulation Of Cell Cycle

scholarly journals A fission yeast homolog of CDC20/p55CDC/Fizzy is required for recovery from DNA damage and genetically interacts with p34cdc2.

1997 ◽  
Vol 17 (2) ◽  
pp. 742-750 ◽  
Author(s):  
T Matsumoto
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Fission Yeast ◽  
Cell Cycle Progression ◽  
Eukaryotic Cell ◽  
Cycle Progression ◽  
Cell Cycle Delay ◽  
Successful Recovery ◽  
Synthetically Lethal

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.

Isoxazole derivatives of 6-fluoro-N-(6-methoxybenzo[d]thiazol-2-yl)benzo[d]thiazol-2-amine and N-(pyrimidin-2-yl)benzo[d]thiazol-2-amine: regulation of cell cycle and apoptosis by p53 activation via mitochondrial-dependent pathways

MedChemComm ◽  
2014 ◽  
Vol 5 (11) ◽  
pp. 1744-1750 ◽  
Author(s):  
Ravindra M. Kumbhare ◽  
Tulshiram L. Dadmal ◽  
T. Anjana Devi ◽  
Dinesh Kumar ◽  
Umesh B. Kosurkar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
P53 Activation ◽  
Regulation Of Cell Cycle ◽  
Derivatives Of ◽  
Isoxazole Derivatives

The compounds depicted were shown to induce DNA damage and activate p53, which in turn activates Bax and decreases Bcl2 levels. This resulted in apoptosis in Colo205 cells.

scholarly journals TIF1 Proteins in Genome Stability and Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2094 ◽  
Author(s):  
Roisin M. McAvera ◽  
Lisa J. Crawford
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Binding Proteins ◽  
Chromatin Binding ◽  
Cycle Progression ◽  
E3 Ligases ◽  
Cancer Types ◽  
Cycle Regulation

Genomic instability is a hallmark of cancer cells which results in excessive DNA damage. To counteract this, cells have evolved a tightly regulated DNA damage response (DDR) to rapidly sense DNA damage and promote its repair whilst halting cell cycle progression. The DDR functions predominantly within the context of chromatin and requires the action of chromatin-binding proteins to coordinate the appropriate response. TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases. All four TIF1 proteins are aberrantly expressed across numerous cancer types, and increasing evidence suggests that TIF1 family members can function to maintain genome stability by mediating chromatin-based responses to DNA damage. This review provides an overview of the TIF1 family in cancer, focusing on their roles in DNA repair, chromatin regulation and cell cycle regulation.

scholarly journals Identification of Primary Transcriptional Regulation of Cell Cycle-Regulated Genes upon DNA Damage

Cell Cycle ◽  
2007 ◽  
Vol 6 (8) ◽  
pp. 972-981 ◽  
Author(s):  
Tong Zhou ◽  
Jeff Chou ◽  
Thomas E. Mullen ◽  
Rani Elkon ◽  
Yingchun Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Transcriptional Regulation ◽  
Regulation Of Cell Cycle

scholarly journals Pin1 inhibits PP2A-mediated Rb dephosphorylation in regulation of cell cycle and S-phase DNA damage

2015 ◽  
Vol 6 (2) ◽  
pp. e1640-e1640 ◽  
Author(s):  
Y Tong ◽  
H Ying ◽  
R Liu ◽  
L Li ◽  
J Bergholz ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
S Phase ◽  
Regulation Of Cell Cycle

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death in Saccharomyces cerevisiae

2012 ◽  
Vol 83 (1) ◽  
pp. 225-234 ◽  
Author(s):  
Shannon K. Stevens ◽  
Amy P. Strehle ◽  
Rebecca L. Miller ◽  
Sarah H. Gammons ◽  
Kyle J. Hoffman ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Ruthenium Complex ◽  
Cell Cycle Delay
Sign in / Sign up

Export Citation Format

Share Document