Unrepairable DNA double-strand breaks that are generated by ionising radiation determine the cell fate of normal human cells

Noda, Asao; Hirai, Yuko; Hamasaki, Koji; Mikami, Hiroshi; Nakamura, Nori; Kodama, Y.

doi:10.1242/jcs.101006

Cited by 41 publications

(58 citation statements)

References 36 publications

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“…2), indicating that persistent unrepairable damage did not induce apoptosis in damage-carrying Sertoli cells. This is in accordance with the accumulation of regions of unrepairable complex DNA damage in tissues in vivo, especially such with cells with long life spans that are resistant to apoptosis, like cells in the ageing brain, pancreas, skin, and kidney (Noda et al 2012; Ahmed et al 2012). …”

Section: Discussionsupporting

confidence: 58%

DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts

et al. 2016

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Noncycling and terminally differentiated (TD) cells display differences in radiosensitivity and DNA damage response. Unlike other TD cells, Sertoli cells express a mixture of proliferation inducers and inhibitors in vivo and can reenter the cell cycle. Being in a G1-like cell cycle stage, TD Sertoli cells are expected to repair DSBs by the error-prone nonhomologous end-joining pathway (NHEJ). Recently, we have provided evidence for the involvement of Ku-dependent NHEJ in protecting testis cells from DNA damage as indicated by persistent foci of the DNA double-strand break (DSB) repair proteins phospho-H2AX, 53BP1, and phospho-ATM in TD Sertoli cells of Ku70-deficient mice. Here, we analyzed the kinetics of 53BP1 foci induction and decay up to 12 h after 0.5 Gy gamma irradiation in DNA-PKcs-deficient (Prkdc scid) and wild-type Sertoli cells. In nonirradiated mice and Prkdc scid Sertoli cells displayed persistent DSBs foci in around 12 % of cells and a fivefold increase in numbers of these DSB DNA damage-related foci relative to the wild type. In irradiated mice, Prkdc scid Sertoli cells showed elevated levels of DSB-indicating foci in 82 % of cells 12 h after ionizing radiation (IR) exposure, relative to 52 % of irradiated wild-type Sertoli cells. These data indicate that Sertoli cells respond to and repair IR-induced DSBs in vivo, with repair kinetics being slow in the wild type and inefficient in Prkdc scid. Applying the same dose of IR to Prdkc −/− and Ku −/− mouse embryonic fibroblast (MEF) cells revealed a delayed induction of 53BP1 DSB-indicating foci 5 min post-IR in Prdkc −/− cells. Inefficient DSB repair was evident 7 h post-IR in DNA-PKcs-deficient cells, but not in Ku −/− MEFs. Our data show that quiescent Sertoli cells repair genotoxic DSBs by DNA-PKcs-dependent NEHJ in vivo with a slower kinetics relative to somatic DNA-PKcs-deficient cells in vitro, while DNA-PKcs deficiency caused inefficient DSB repair at later time points post-IR in both conditions. These observations suggest that DNA-PKcs contributes to the fast and slow repair of DSBs by NHEJ.Electronic supplementary materialThe online version of this article (doi:10.1007/s00412-016-0590-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 58%

DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts

et al. 2016

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“…Typically, DDR foci can already be detected 3 min after irradiation, reaching a maximum size and number 30 min after exposure to IR and dissociating within 24 h 43 . However, the persistence of DDR foci leads to apoptosis or cellular senescence 29 , 44 …”

Section: Resultsmentioning

confidence: 99%

Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers

et al. 2014

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Cells respond to genotoxic stress by activating the DNA damage response (DDR). When injury is severe or irreparable, cells induce apoptosis or cellular senescence to prevent transmission of the lesions to the daughter cells upon cell division. Resistance to apoptosis is a hallmark of cancer that challenges the efficacy of cancer therapy. In this work, the effects of ionizing radiation on apoptosis-resistant E1A + E1B transformed cells were investigated to ascertain whether the activation of cellular senescence could provide an alternative tumor suppressor mechanism. We show that irradiated cells arrest cell cycle at G2/M phase and resume DNA replication in the absence of cell division followed by formation of giant polyploid cells. Permanent activation of DDR signaling due to impaired DNA repair results in the induction of cellular senescence in E1A + E1B cells. However, irradiated cells bypass senescence and restore the population by dividing cells, which have near normal size and ploidy and do not express senescence markers. Reversion of senescence and appearance of proliferating cells were associated with downregulation of mTOR, activation of autophagy, mitigation of DDR signaling, and expression of stem cell markers.

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“…Up to half of the persistent DNA damage foci in cells undergoing senescence in response to ionising radiation are associated with telomeres (Hewitt et al, 2012). This telomeric DNA damage is refractory to repair and as a result causes persistent DNA damage signalling (Fumagalli et al, 2012;Noda et al, 2012). Indeed, p53-oscillations might be different in cells with similar amount of DNA damage foci (Loewer et al, 2013), indicating that the location of DNA damage, or its type or repair state, might influence p53 dynamics.…”

Section: What Determines Cellular Fate?mentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

252

272

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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Unrepairable DNA double-strand breaks that are generated by ionising radiation determine the cell fate of normal human cells

Cited by 41 publications

References 36 publications

DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts

DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts

Sustained activation of DNA damage response in irradiated apoptosis-resistant cells induces reversible senescence associated with mTOR downregulation and expression of stem cell markers

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

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