Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks

Lee, Dong-Hyun; Acharya, Sanket S.; Kwon, Mijung; Drané, Pascal; Guan, Yalin; Adelmant, Guillaume; Kalev, Peter; Shah, Jagesh V.; Pellman, David; Marto, Jarrod A.; Chowdhury, Dipanjan

doi:10.1016/j.molcel.2014.03.020

Cited by 108 publications

(140 citation statements)

References 48 publications

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“…42 Artificial restoration of 53BP binding to DSBs in mitotic cells by expressing a non-phorphorylatable 53BP1 mutant leads to sister telomere fusion due to NHEJ repair followed by chromosome segregation errors. 43,44 Although the efficiency of DSB repair during mitosis is much lower than in interphase, a substantial proportion of the DSBs is repaired during mitosis and the repair process is regulated by mechanisms other than those active in other cell-cycle phases. XRCC4 does not localize to mitotic chromosomes but DNA ligase IV associates with chromosomes.…”

Section: Discussionmentioning

confidence: 99%

DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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Because low levels of DNA double strand breaks (DSBs) appear not to activate the ATM-mediated prophase I checkpoint in full-grown oocytes, there may exist mechanisms to protect chromosome integrity during meiotic maturation. Using live imaging we demonstrate that low levels of DSBs induced by the radiomimetic drug Neocarzinostatin (NCS) increase the incidence of chromosome fragments and lagging chromosomes but do not lead to APC/C activation and anaphase onset delay. The number of DSBs, represented by gH2AX foci, significantly decreases between prophase I and metaphase II in both control and NCS-treated oocytes. Transient treatment with NCS increases >2-fold the number of DSBs in prophase I oocytes, but less than 30% of these oocytes enter anaphase with segregation errors. MRE11, but not ATM, is essential to detect DSBs in prophase I and is involved in H2AX phosphorylation during metaphase I. Inhibiting MRE11 by mirin during meiotic maturation results in anaphase bridges and also increases the number of gH2AX foci in metaphase II. Compromised DNA integrity in mirin-treated oocytes indicates a role for MRE11 in chromosome integrity during meiotic maturation.

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Section: Discussionmentioning

confidence: 99%

DNA damage response during mouse oocyte maturation

Mayer

Baran

Sakakibara³

et al. 2016

Cell Cycle

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“…41 Protein phosphatase PP4 has recently been reported to dephosphorylate pS1618-53BP1 during mitotic exit. 50 Thus the interaction between 53BP1 and Plk1 and phosphorylation of the S1618 is tightly spatiotemporally regulated during mitosis.…”

Section: Discussionmentioning

confidence: 99%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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Abbreviations: 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; Plk1, Polo-like kinase 1; H2AX, histone variant H2AX; IR -ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS -neocarzinostatin; NZ -nocodazole; PTIP, PAX transactivation activation domain-interacting protein; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF8, RING finger protein 8; RNF168, RING finger protein 168.In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and nonhomologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

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“…Cdk1 phosphorylates the ubiquitin ligase RNF8 (at S198) to prevent the formation of K63-linked polyubiquitin at damage sites (Orthwein et al, 2014). Additional phosphorylation of residues T1609 and S1618 of 53BP1 by Plk1 and an unidentified kinase interferes with its recruitment to damaged DNA (Lee et al, 2014;van Vugt et al, 2010). Phosphorylation of RNF8 and 53BP1 prevents DNA repair during mitosis (Orthwein et al, 2014).…”

Section: Mitosismentioning

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

247

263

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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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Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks

Cited by 108 publications

References 48 publications

DNA damage response during mouse oocyte maturation

DNA damage response during mouse oocyte maturation

Polo-like kinase 1 inhibits DNA damage response during mitosis

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

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