Recombination-dependent concatemeric viral DNA replication

Piano, Ambra Lo; Martínez‐Jiménez, María I.; Zecchi, Lisa; Ayora, Silvia

doi:10.1016/j.virusres.2011.06.009

Cited by 46 publications

(50 citation statements)

References 187 publications

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“…Mounting evidence indicates that viruses exploit the cellular DNA damage response in order to facilitate the replication of their own genetic material (22,23), and recombination-dependent replication has been previously described as a viable and efficient method for production for some virus types (24). In fact, DNA viruses such as simian virus 40 (SV40) (25), herpes simplex virus 1 (HSV-1) (26-28), Epstein-Barr virus (EBV) (29,30), and Kaposi's sarcoma-associated herpesvirus (KSHV) (31) have exhibited the use of replication-associated recombination in the synthesis of their genomes during infection.…”

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confidence: 99%

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

Chappell

Gautam

et al. 2016

J Virol

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High-risk human papillomavirus 31 (HPV31)-positive cells exhibit constitutive activation of the ATM-dependent DNA damage response (DDR), which is necessary for productive viral replication. In response to DNA double-strand breaks (DSBs), ATM activation leads to DNA repair through homologous recombination (HR), which requires the principal recombinase protein Rad51, as well as BRCA1. Previous studies from our lab demonstrated that Rad51 and BRCA1 are expressed at high levels in HPV31-positive cells and localize to sites of viral replication. These results suggest that HPV may utilize ATM activity to increase HR activity as a means to facilitate viral replication. In this study, we demonstrate that high-risk HPV E7 expression alone is sufficient for the increase in Rad51 and BRCA1 protein levels. We have found that this increase occurs, at least in part, at the level of transcription. Studies analyzing protein stability indicate that HPV may also protect Rad51 and BRCA1 from turnover, contributing to the overall increase in cellular levels. We also demonstrate that Rad51 is bound to HPV31 genomes, with binding increasing per viral genome upon productive replication. We have found that depletion of Rad51 and BRCA1, as well as inhibition of Rad51's recombinase activity, abrogates productive viral replication upon differentiation. Overall, these results indicate that Rad51 and BRCA1 are required for the process of HPV31 genome amplification and suggest that productive replication occurs in a manner dependent upon recombination. IMPORTANCEProductive replication of HPV31 requires activation of an ATM-dependent DNA damage response, though how ATM activity contributes to replication is unclear. Rad51 and BRCA1 play essential roles in repair of double-strand breaks, as well as the restart of stalled replication forks through homologous recombination (HR). Given that ATM activity is required to initiate HR repair, coupled with the requirement of Rad51 and BRCA1 for productive viral replication, our findings suggest that HPV may utilize ATM activity to ensure localization of recombination factors to productively replicating viral genomes. The finding that E7 increases the levels of Rad51 and BRCA1 suggests that E7 contributes to productive replication by providing DNA repair factors required for viral DNA synthesis. Our studies not only imply a role for recombination in the regulation of productive HPV replication but provide further insight into how HPV manipulates the DDR to facilitate the productive phase of the viral life cycle. H uman papillomaviruses (HPVs) are small double-stranded DNA viruses approximately 8 kb in size that exhibit a preferential tropism for epithelial cells. High-risk mucosal HPV subtypes are the causative agents of cervical cancer and have been increasingly associated with anogenital, oropharyngeal, and head and neck cancers (1). The life cycle of HPV is intimately linked to the differentiation of its host cell, the keratinocyte (2). After exposure through a microwound in the stratified ep...

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Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

Chappell

Gautam

et al. 2016

J Virol

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“…In tailed dsDNA bacteriophages and herpesviruses, the newly synthesized viral DNA in host cells exists as tandem concatemers, each composed of multiple copies of unit-length genome (6,7). The viral DNA-packaging motor (also known as terminase large subunit or large terminase) cleaves concatemeric viral DNA into units of or near the genomic length and pumps each into a preformed capsid precursor termed procapsid powered by ATP hydrolysis (2,6,8).…”

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Structures of the phage Sf6 large terminase provide new insights into DNA translocation and cleavage

Zhao

Christensen

Kamau

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

102

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Many DNA viruses use powerful molecular motors to cleave concatemeric viral DNA into genome-length units and package them into preformed procapsid powered by ATP hydrolysis. Here we report the structures of the DNA-packaging motor gp2 of bacteriophage Sf6, which reveal a unique clade of RecA-like ATPase domain and an RNase H-like nuclease domain tethered by a regulatory linker domain, exhibiting a strikingly distinct domain arrangement. The gp2 structures complexed with nucleotides reveal, at the atomic detail, the catalytic center embraced by the ATPase domain and the linker domain. The gp2 nuclease activity is modulated by the ATPase domain and is stimulated by ATP. An extended DNA-binding surface is formed by the linker domain and the nuclease domain. These results suggest a unique mechanism for translation of chemical reaction into physical motion of DNA and provide insights into coordination of DNA translocation and cleavage in a viral DNA-packaging motor, which may be achieved via linker-domain-mediated interdomain communication driven by ATP hydrolysis.terminase | virus assembly | genome packaging M ost double-stranded DNA (dsDNA) viruses package their genome into preformed protein shells in an active manner using virally encoded molecular motors, as in tailed dsDNA bacteriophages (1, 2), herpesviruses (3), adenoviruses (4), and poxviruses (5). In tailed dsDNA bacteriophages and herpesviruses, the newly synthesized viral DNA in host cells exists as tandem concatemers, each composed of multiple copies of unit-length genome (6, 7). The viral DNA-packaging motor (also known as terminase large subunit or large terminase) cleaves concatemeric viral DNA into units of or near the genomic length and pumps each into a preformed capsid precursor termed procapsid powered by ATP hydrolysis (2,6,8).The DNA-packaging motors of dsDNA bacteriophages package DNA highly densely into the capsid, resulting in an internal pressure of as high as 50 atmospheres, more than 10 times that found in any other living system (9, 10). These molecular motors can work against a force larger than 50 pN and package DNA at high rates, placing them among the most powerful molecular motors in nature (9, 11). Most phage DNA packaging motor proteins are bifunctional enzymes that integrate two types of enzymatic activities, the ATPase and the nuclease, as required by the concatemeric nature of the packaging substrates. Resolving DNA concatemers into units and packaging into procapsid must be precisely coordinated, and the nuclease activity may only be activated at the initiation step of DNA packaging and upon completion of each packaging cycle.Structures of phage T4 terminase large subunit gp17 revealed an ATPase domain belonging to the additional-strand catalytic glutamate (ASCE) superfamily, and a model for DNA translocation dependent on electrostatic forces was proposed (12, 13). Nevertheless, this model was not supported by the structure of phage SPP1 G2P nuclease domain, as the proposed secondary DNA-binding surface during DNA translocation...

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“…From the results obtained with E. coli enzymes, it is believed that bacterial HJ resolvases work in concert with RuvAB. However, recent data from other bacteria suggest that the in vivo role of ubiquitous HJ translocases (RecG and RuvAB) might not be conserved: (i) the absence of both branch migration translocases, RecG and RuvAB, is synthetically lethal in B. subtilis (Firmicutes phylum) or Neisseria gonorrhoeae (representative of ␤-Proteobacteria class) (24 -26); (ii) ruvAB and recG show a synergistic defect in DNA repair in E. coli cells (␥-Proteobacteria class); (iii) recG suppresses the recombination defect of the ruvB mutations in Helicobacter pylori (representative of ⑀-Proteobacteria Class) (27); (iv) ruvAB is synthetically lethal in the recU context (24); (v) the resolvases from phages or Archaea seem to act independently of the presence of a branch migration helicase (6,12,28).…”

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Interaction of Branch Migration Translocases with the Holliday Junction-resolving Enzyme and Their Implications in Holliday Junction Resolution

Cañas

Suzuki

Marchisone

et al. 2014

Journal of Biological Chemistry

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Background: Bacillus subtilis RuvAB and RecG translocases and RecU resolvase are crucial in homologous recombination. Results: RecU interacts with RuvB and re-localizes it at a Holliday junction (HJ). RuvB stimulates RecU. RecG and RuvAB unwind HJs. Conclusion: A RecU⅐HJ⅐RuvAB complex might be formed. Significance: RecU, which interacts with RecA, may help to discriminate between RuvAB and RecG at HJs.

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Recombination-dependent concatemeric viral DNA replication

Cited by 46 publications

References 187 publications

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

Structures of the phage Sf6 large terminase provide new insights into DNA translocation and cleavage

Interaction of Branch Migration Translocases with the Holliday Junction-resolving Enzyme and Their Implications in Holliday Junction Resolution

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