A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses

Lilley, Caroline E.; Chaurushiya, Mira S.; Boutell, Chris; Landry, Sébastien; Suh, Junghae; Panier, Stephanie; Everett, Roger D.; Stewart, Grant S.; Durocher, Daniel; Weitzman, Matthew D.

doi:10.1038/emboj.2009.400

Cited by 156 publications

(179 citation statements)

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“…On the other hand, HSV-1 infection results in the degradation of DNA-PKcs in many cell types (28,40), and viral yields increase severalfold in cells deficient for DNA-PKcs and Ku70 (40,60), indicating that at least some components of NHEJ may be inhibitory for viral growth. Interestingly, cellular ubiquitin ligases RNF8 and RNF168 (components of the ATM pathway) are degraded during infection (31). Thus, HSV has apparently evolved a very complex interaction with the host DNA damage response pathways, activating some components and inactivating others.…”

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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“…For instance, key regulators of DDR focus formation-such as ATM, ATR, MRE11, NBS1, and RNF168-are mutated in severe genome instability disorders (Jackson and Bartek 2009;Ciccia and Elledge 2010), and MRN, RNF8, and RNF168 have been identified as prominent targets during viral infection (Carson et al 2009;Lilley et al 2010). In some cases, however, the ability of certain DDR factors to compensate for one another has hindered evaluation of their functional requirements.…”

Section: Dynamics Of Dna Damage Foci Genes and Development 421mentioning

confidence: 99%

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Polo¹,

Jackson²

2011

Genes Dev.

969

946

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Genome integrity is constantly monitored by sophisticated cellular networks, collectively termed the DNA damage response (DDR). A common feature of DDR proteins is their mobilization in response to genotoxic stress. Here, we outline how the development of various complementary methodologies has provided valuable insights into the spatiotemporal dynamics of DDR protein assembly/disassembly at sites of DNA strand breaks in eukaryotic cells. Considerable advances have also been made in understanding the underlying molecular mechanisms for these events, with post-translational modifications of DDR factors being shown to play prominent roles in controlling the formation of foci in response to DNA-damaging agents. We review these regulatory mechanisms and discuss their biological significance to the DDR.

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“…1 and 2). Ubiquitylation is functionally linked to transcriptional silencing (3)(4)(5), DNA damage signal amplification, and DNA repair (2,(6)(7)(8)(9)(10)(11)(12)(13)(14). Recent studies indicate that the ubiquitin landscape at damaged chromatin is very dynamic, and a significant repertoire of deubiquitylating enzymes (DUB) or ubiquitin-specific proteases (USP) are emerging as critical regulators of ubiquitin signaling.…”

Section: Introductionmentioning

confidence: 99%

Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair

et al. 2014

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The BRCA1-associated deubiquitylase BAP1 is mutated in several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis. In this study, we present evidence that BAP1 functions as part of the DNA damage response (DDR). We found that BAP1 mediates rapid poly(ADP-ribose)-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA damage. Furthermore, we identified BAP1 as a phosphorylation target for the DDR kinase ATM. Functionally, BAP1 promoted repair of DNA double-strand breaks, enhancing cell survival after DNA damage. Our results highlight the importance of ubiquitin turnover at sites of DNA damage, and they provide a mechanism to account for the tumorsuppressive function of BAP1. Cancer Res; 74(16); 4282-94. Ó2014 AACR.

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A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses

Cited by 156 publications

References 100 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

Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications

Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair

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