Roles for NBS1 in Alternative Nonhomologous End-Joining of V(D)J Recombination Intermediates

Deriano, Ludovic; Stracker, Travis H.; Baker, Annalee M; Petrini, John H.J.; Roth, David B.

doi:10.1016/j.molcel.2009.03.009

Cited by 100 publications

(113 citation statements)

References 68 publications

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“…Rad51 nucleofilaments are capable of detecting homology in duplex DNA and participating in strand invasion to initiate HRR. It is interesting that, in addition to its role in the ATM-mediated HRR pathways, MRN has also been shown to participate in end resection in the classical NHEJ pathway (16) and the alternative (A-NHEJ) pathway (8). MRN also associates with telomeres and participates in the maintenance of normal telomere length (22,72).…”

Section: Discussionmentioning

confidence: 99%

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

Balasubramanian

Bai

Buchek

et al. 2010

J Virol

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The herpes simplex virus type 1 (HSV-1) alkaline nuclease, encoded by the UL12 gene, plays an important role in HSV-1 replication, as a UL12 null mutant displays a severe growth defect. The HSV-1 alkaline exonuclease UL12 interacts with the viral single-stranded DNA binding protein ICP8 and promotes strand exchange in vitro in conjunction with ICP8. We proposed that UL12 and ICP8 form a two-subunit recombinase reminiscent of the phage lambda Red ␣/␤ recombination system and that the viral and cellular recombinases contribute to viral genome replication through a homologous recombination-dependent DNA replication mechanism. To test this hypothesis, we identified cellular interaction partners of UL12 by using coimmunoprecipitation. We report for the first time a specific interaction between UL12 and components of the cellular MRN complex, an important factor in the ATM-mediated homologous recombination repair (HRR) pathway. This interaction is detected early during infection and does not require viral DNA or other viral or cellular proteins. The region of UL12 responsible for the interaction has been mapped to the first 125 residues, and coimmunoprecipitation can be abolished by deletion of residues 100 to 126. These observations support the hypothesis that cellular and viral recombination factors work together to promote efficient HSV-1 growth.The herpes simplex virus (HSV) genome replicates in the nucleus of an infected host cell, resulting in the production of longer-than-unit-length head-to-tail concatemers of viral DNA. Production of infectious virus requires the processing of concatemeric DNA into unit-length genomes by the packaging machinery followed by encapsidation into preassembled capsids (63). Several lines of evidence suggest that recombination plays a role in concatemer formation (69). Genomic inversions, proposed to occur through recombination, can be detected very early during infection, and these inversions require sequence homology (2,23,56). In addition, replication intermediates in HSV type 1 (HSV-1)-infected cells adopt a complex nonlinear structure that does not migrate in a pulsed-field gel, even after digestion with an enzyme that cuts once per unit length of the genome (1,33,51,71). Electron micrographs have revealed that replication intermediates are branched and contain Y-and X-shaped junctions (19,52). Furthermore, high levels of recombination have been reported not only between coinfecting viral strains (4, 17, 50, 62, 66) but also in plasmids containing repeated sequence elements (10, 11). These observations, taken together, are not consistent with a simple rolling circle mechanism of replication and suggest that, reminiscent of the bacteriophages T4 and lambda, HSV-1 utilizes a recombination-dependent replication mechanism to generate concatemeric viral DNA.We have previously reported that virus-encoded proteins are capable of participating in recombination events in vitro. The viral 5Ј-3Ј alkaline exonuclease (UL12) and the single-strand binding protein (ICP8) together mediate stra...

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Section: Discussionmentioning

confidence: 99%

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

Balasubramanian

Bai

Buchek

et al. 2010

J Virol

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“…This apparent contradiction has been resolved by a series of reports that provide evidence for a role for MRN in NHEJ. This complex plays a role in NHEJ during V(D)J recombination in developing immunocytes (19) and during isotype class switching (20). Silencing Mre11 reduced the efficiency of both the canonical and alternate pathways of NHEJ independent of ATM, mutated in the human genetic disorder ataxia-telangiectasia (A-T) (21,22).…”

mentioning

confidence: 99%

ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control

Gatei

Jakob

Chen

et al. 2011

Journal of Biological Chemistry

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“…The regulatory mechanisms proposed here are likely to be relevant in higher eukaryotes, since both ATM and the MRN complex positively regulate DNA repair through NHEJ. [57][58][59] In this regard, it will be exciting to determine whether the mechanisms described herein contribute to the DNA damage sensitivity and poor prognostic associated with human diseases such as the Nijmegen breakage syndrome and ataxia telangiectasia.…”

Section: Discussionmentioning

confidence: 99%

Cdk1-dependent regulation of the Mre11 complex couples DNA repair pathways to cell cycle progression

Simoneau¹,

Robellet²,

Ladouceur³

et al. 2014

Cell Cycle

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Roles for NBS1 in Alternative Nonhomologous End-Joining of V(D)J Recombination Intermediates

Cited by 100 publications

References 68 publications

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

Physical Interaction between the Herpes Simplex Virus Type 1 Exonuclease, UL12, and the DNA Double-Strand Break-Sensing MRN Complex

ATM Protein-dependent Phosphorylation of Rad50 Protein Regulates DNA Repair and Cell Cycle Control

Cdk1-dependent regulation of the Mre11 complex couples DNA repair pathways to cell cycle progression

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