2016
DOI: 10.18632/aging.100883
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Abstract: Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair an… Show more

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Cited by 11 publications
(12 citation statements)
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References 71 publications
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“…While males may exhibit greater DNA damage than females, they may not necessarily activate senescence more frequently. DNA damage activates DNA-damage response (DDR) kinases, such as ATM or ATR [253,283]. When the damage is determined as irreparable, DDR kinases upregulate the p53-p21 and p16 INK4a -Rb pathways, resulting in either senescence or apoptosis [253,283].…”
Section: Sex Differences In Senescencementioning
confidence: 99%
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“…While males may exhibit greater DNA damage than females, they may not necessarily activate senescence more frequently. DNA damage activates DNA-damage response (DDR) kinases, such as ATM or ATR [253,283]. When the damage is determined as irreparable, DDR kinases upregulate the p53-p21 and p16 INK4a -Rb pathways, resulting in either senescence or apoptosis [253,283].…”
Section: Sex Differences In Senescencementioning
confidence: 99%
“…DNA damage activates DNA-damage response (DDR) kinases, such as ATM or ATR [253,283]. When the damage is determined as irreparable, DDR kinases upregulate the p53-p21 and p16 INK4a -Rb pathways, resulting in either senescence or apoptosis [253,283]. Interestingly, under some circumstances, damaged cells remain proliferative despite these protective mechanisms.…”
Section: Sex Differences In Senescencementioning
confidence: 99%
“…To further validate the persistence of the sub-G1 population over time we irradiated MRC5 cells with a dose of 20 Gy and monitored them for up to 52 days. Interestingly, after this time there was still no sign of cell death [ 24 ], the sub-G1 fraction reached more than 70% and cells exhibited clear enlargement of nuclei and reduction of DAPI fluorescence intensity, suggesting reduced DNA content ( Supplementary Figure S4A, S4B, S4C ).…”
Section: Resultsmentioning
confidence: 99%
“…The above described non-lethal DNA cleavage provides for the first time an explanation why at a certain time point after IR-induced DNA-damage cells can no longer be released from cell cycle arrest. For example, p21 silencing is able to release the IR-induced cell cycle arrest up to 12 days, but not after 21 days [ 24 , 25 ], a phenomenon sometimes called deep senescence. Therefore, we investigated whether DNA cleavage is necessary for this deep senescence phenotype.…”
Section: Resultsmentioning
confidence: 99%
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