Contribution of the 3′- to 5′-Exonuclease Activity of Herpes Simplex Virus Type 1 DNA Polymerase to the Fidelity of DNA Synthesis

Song, Liping; Chaudhuri, Murari; Knopf, Charles W.; Parris, Deborah S.

doi:10.1074/jbc.m309848200

Cited by 44 publications

(54 citation statements)

References 30 publications

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“…Further experiments will be required to identify the actual rate-limiting step(s) for extension by the exo -pol beyond the AP site. However, it is interesting to note that there also was an absence of a burst and a very slow rate for extension of mismatches during processive synthesis by the exo -pol [9]. As suggested in that study, we think it likely that the P/T is held in the exo site for an extended period of time due to the inability of the pol to cleave the last nucleotide from the primer.…”

Section: Mechanisms By Which Parameters Other Than Exo Activity Impedmentioning

confidence: 50%

“…The WT and exo -mutant (D368A) HSV-1 pol genes (UL30) were expressed by infecting Spodoptera frugiperda 9 (Sf9) insect cells with recombinant baculoviruses containing the respective genes [9,29]. The baculoviruses containing the WT and D368A HSV-1 pol genes were gifts from Bob Lehman (Stanford University) and Charles Knopf (University of Heidelberg), respectively.…”

Section: Preparation Of Enzymesmentioning

confidence: 99%

“…The baculoviruses containing the WT and D368A HSV-1 pol genes were gifts from Bob Lehman (Stanford University) and Charles Knopf (University of Heidelberg), respectively. Enzymes were purified to >95% purity as detailed previously [9,29] except that whole cell extracts were used.…”

Section: Preparation Of Enzymesmentioning

confidence: 99%

“…The 1235-amino-acid HSV-1 DNA polymerase catalytic subunit (pol), a B family polymerase, is encoded by the UL30 gene and contains conserved 5' to 3' polymerizing and 3' to 5' exonuclease (exo) domains [2][3][4][5][6]. Functional analysis of proteins containing mutations in the exo domain indicates that the polymerizing and exo activities can function independently [7][8][9]. The region encoding the C-terminal domain of HSV-1 pol is poorly conserved.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms by which herpes simplex virus DNA polymerase limits translesion synthesis through abasic sites

et al. 2008

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Results suggest a high probability that abasic (AP) sites occur at least once per herpes simplex virus type 1 (HSV-1) genome. The parameters that control the ability of HSV-1 DNA polymerase (pol) to engage in AP translesion synthesis (TLS) were examined because AP lesions could influence the completion and fidelity of viral DNA synthesis. Pre-steady-state kinetic experiments demonstrated that wild-type (WT) and exonuclease-deficient (exo -) pol could incorporate opposite an AP lesion, but full TLS required absence of exo function. Virtually all of the WT pol was bound at the exo site to AP-containing P/Ts at equilibrium, and the pre-steady-state rate of excision by WT pol was higher on AP-containing than on matched DNA. However, several factors influencing polymerization work synergistically with exo activity to prevent HSV-1 pol from engaging in TLS. Although the pre-steady-state catalytic rate constant for insertion of dATP opposite a T or AP site was similar, ground-state binding affinity of dATP for insertion opposite an AP site was reduced 3−9-fold. Single-turnover running-start experiments demonstrated a reduced proportion of P/Ts extended to the AP site compared to the preceding site during processive synthesis by WT or exo -pol. Only the exo -pol engaged in TLS, though inefficiently and without burst kinetics, suggesting a much slower rate-limiting step for extension beyond the AP site.

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Section: Mechanisms By Which Parameters Other Than Exo Activity Impedmentioning

confidence: 50%

Section: Preparation Of Enzymesmentioning

confidence: 99%

Section: Preparation Of Enzymesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms by which herpes simplex virus DNA polymerase limits translesion synthesis through abasic sites

et al. 2008

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“…It appears that the overall replication fidelity is high, and existing genetic variability may be created by recombination between a limited number of strains rather than random replication errors (12)(13)(14). The contribution of the DNA polymerase to replication fidelity has been thoroughly examined, but cellular mechanisms contributing to the genetic stability of herpesviruses have, with few exceptions, not been extensively looked at (15)(16)(17)(18). It has been noted that several cellular repair proteins co-localize with viral replication proteins in a limited number of replication foci (19 -21).…”

mentioning

confidence: 99%

Contributions of Nucleotide Excision Repair, DNA Polymerase η, and Homologous Recombination to Replication of UV-irradiated Herpes Simplex Virus Type 1

Muylaert

Elias

2010

Journal of Biological Chemistry

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, virus replication was reduced 10 6 -, 400-, and 100-fold, respectively. In DNA polymerase mutant cells HSV-1 plaque efficiency was reduced 10 4 -fold. Furthermore, DNA polymerase was strictly required for virus replication at low multiplicities of infection but dispensable at high multiplicities of infection. Knock down of Rad 51, Rad 52, and Rad 54 levels by RNA interference reduced replication of UV-irradiated HSV-1 150-, 100-, and 50-fold, respectively. We find that transcription-coupled repair efficiently supports expression of immediate early and early genes from UV-irradiated HSV-1 DNA. In contrast, the progression of the replication fork appears to be impaired, causing a severe reduction of late gene expression. Since the HSV-1 replisome does not make use of proliferating cell nuclear antigen, we attribute the replication defect to an inability to perform proliferating cell nuclear antigen-dependent translesion synthesis by polymerase switching at the fork. Instead, DNA polymerase may act during postreplication gap filling. Homologous recombination, finally, might restore the physical and genetic integrity of the virus chromosome.Herpes simplex virus has a linear double-stranded genome, which, upon entry into the eukaryotic nucleus, circularizes and becomes replicated by a replisome consisting of six virus-encoded proteins (1-4). The herpes simplex virus replisome is composed of a DNA polymerase made up from the UL30 and UL42 gene products, a helicase-primase complex encoded by the UL5, UL8, and UL52 genes and a single-stranded DNAbinding protein ICP8, which is a product of the UL29 gene (4, 5). The replisome is loaded on the origins of replication oriS and oriL by a sequence-specific superfamily II DNA helicase termed OBP or UL9 protein (6 -9), and it is capable of processive leading strand DNA synthesis coupled to discontinuous synthesis of lagging strand intermediates (5). Processive polymerization is dependent on the UL42 protein, which is a monomer folded as the proliferating cell nuclear antigen (PCNA) 2 protomer but with no sequence similarity to the cellular processivity factor (10). The UL30 subunit is a proofreading family B DNA polymerase (11). It appears that the overall replication fidelity is high, and existing genetic variability may be created by recombination between a limited number of strains rather than random replication errors (12)(13)(14). The contribution of the DNA polymerase to replication fidelity has been thoroughly examined, but cellular mechanisms contributing to the genetic stability of herpesviruses have, with few exceptions, not been extensively looked at (15-18). It has been noted that several cellular repair proteins co-localize with viral replication proteins in a limited number of replication foci (19 -21). In cells, genomic stability is maintained by an intricate interplay among the replication machinery, repair proteins, and factors controlling the cell cycle (22,23). Viruses are known to interact and interfere with these mechanisms to promote their own replication...

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Glycoprotein targeted therapeutics: a new era of anti‐herpes simplex virus‐1 therapeutics

Antoine

Park

Shukla

2013

Reviews in Medical Virology

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Herpes simplex virus type-1 (HSV-1) is among the most common human pathogens worldwide. Its entry into host cells is an intricate process that relies heavily on the ability of the viral glycoproteins to bind host cellular proteins and to efficiently mediate fusion of the virus envelope with the cell membrane. Acquisition of HSV-1 results in a lifelong latent infection. Due to the cycles of reactivation from a latent state, much emphasis has been placed on the management of infection through the use of DNA synthesis inhibitors. However, new methods are needed to provide more effective treatment at earlier phases of the viral infection and to prevent the development of drug resistance by the virus. This review outlines the infection process and the common therapeutics currently used against the fundamental stages of HSV-1 replication and fusion. The remainder of this article will focus on a new approach for HSV-1 infection control and management, the concept of glycoprotein-receptor targeting.

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Contribution of the 3′- to 5′-Exonuclease Activity of Herpes Simplex Virus Type 1 DNA Polymerase to the Fidelity of DNA Synthesis

Cited by 44 publications

References 30 publications

Mechanisms by which herpes simplex virus DNA polymerase limits translesion synthesis through abasic sites

Mechanisms by which herpes simplex virus DNA polymerase limits translesion synthesis through abasic sites

Contributions of Nucleotide Excision Repair, DNA Polymerase η, and Homologous Recombination to Replication of UV-irradiated Herpes Simplex Virus Type 1

Glycoprotein targeted therapeutics: a new era of anti‐herpes simplex virus‐1 therapeutics

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