Non-homologous end-joining, a sticky affair

Gent, Dik C. van; Burg, Mirjam van der

doi:10.1038/sj.onc.1210871

Cited by 136 publications

(101 citation statements)

References 118 publications

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“…This conclusion is substantiated by the results showing that the human SCID-causing mutant of DNA-PKcs is impaired in its ability to phosphorylate NR4A proteins, although its catalytic activity and autophosphorylation at S2056 are intact. Although some putative DNA-PKcs substrates have been identified, substrates linked to DSB repair at DSB foci have remained elusive (van Gent and van der Burg 2007;Meek et al 2008;Jackson 2009). Intriguingly, our data identify such a phosphorylated target and emphasize the important role of DNA-PKcs substrate phosphorylation at DSBs.…”

Section: Discussionmentioning

confidence: 99%

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

et al. 2011

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DNA-dependent protein kinase (DNA-PK) is a central regulator of DNA double-strand break (DSB) repair; however, the identity of relevant DNA-PK substrates has remained elusive. NR4A nuclear orphan receptors function as sequence-specific DNA-binding transcription factors that participate in adaptive and stress-related cell responses. We show here that NR4A proteins interact with the DNA-PK catalytic subunit and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of poly(ADP-ribose) polymerase-1 (PARP-1). At DNA repair foci, NR4A is phosphorylated by DNA-PK and promotes DSB repair. Notably, NR4A transcriptional activity is entirely dispensable in this function, and core components of the DNA repair machinery are not transcriptionally regulated by NR4A. Instead, NR4A functions directly at DNA repair sites by a process that requires phosphorylation by DNA-PK. Furthermore, a severe combined immunodeficiency (SCID)-causing mutation in the human gene encoding the DNA-PK catalytic subunit impairs the interaction and phosphorylation of NR4A at DSBs. Thus, NR4As represent an entirely novel component of DNA damage response and are substrates of DNA-PK in the process of DSB repair.

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Section: Discussionmentioning

confidence: 99%

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

et al. 2011

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“…14 The majority of the remaining patients show hypersensitivity for ionizing radiation (IR), suggesting a defect in the NHEJ pathway of DNA DSB repair. 15 Mutations in the Artemis, LIG4 and DNA-PKcs genes have been identified in these patients. 14,[16][17][18][19] Furthermore, mutations in the XLF gene have been found in radiosensitive patients with growth retardation, microcephaly and immunodeficiency due to profound T-and B-cell lymphocytopenia.…”

Section: Introductionmentioning

confidence: 98%

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

IJspeert

Lankester

et al. 2011

Genes Immun

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Artemis deficiency is known to result in classical TÀBÀ severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical TÀBÀ SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5 0 splice-site or an intronic point mutation creating a novel 3 0 splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 3 0 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts.

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“…4 Ligation of the broken DNA ends is accomplished by the Lig4/Lif1 complex in S. cerevisiae and Lig4/XRCC4 and XLF/Cernunnos factors in mammals. [5][6][7] Due to nucleolytic processing of DNA ends to make them compatible for subsequent ligation, NHEJ can result in short deletions, and thus this process is error-prone. 4 Homologous recombination (HR) functions primarily in the S/G 2 phase of the cell cycle, and it relies on sequence homology from an undamaged sister chromatid or a homologous DNA sequence to use as a template for copying the missing information.…”

Section: Introductionmentioning

confidence: 99%

Opening the DNA repair toolbox: Localization of DNA double strand breaks to the nuclear periphery

Oza¹,

Peterson²

2010

Cell Cycle

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E fficient repair of DNA double strand breaks is essential for cells to avoid increased mutation rates, genomic instability, and even cell death. Consequently, cells have evolved multiple mechanisms for rapidly repairing these DNA lesions, including error-free homologous recombination as well as error-prone pathways such as nonhomologous end joining. What happens to DSBs that are repaired inefficiently or not at all? Recently, several studies in budding yeast have shown that these more recalcitrant DSBs are localized to the nuclear periphery through interactions between the nuclear envelope protein, Mps3, and proteins associated with DSB chromatin. Why these DSBs are tethered to the nuclear periphery is still not clear, though the current view is that alternative repair pathways may be activated at the periphery in a final attempt to repair the lesion. In this Extra View, we discuss these recent reports, and we show that the Est1 component of the telomerase machinery plays an essential role in anchoring DSB chromatin to the nuclear envelope protein, Mps3.

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Non-homologous end-joining, a sticky affair

Cited by 136 publications

References 118 publications

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

Opening the DNA repair toolbox: Localization of DNA double strand breaks to the nuclear periphery

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