Replication of bovine papillomavirus type 1 origin-containing DNA in crude extracts and with purified proteins.

Müller, F.; Seo, Yeon‐Soo; Hurwitz, Jerard

doi:10.1016/s0021-9258(17)32524-3

Cited by 61 publications

(4 citation statements)

References 49 publications

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“…Pols a and d, PCNA, RF-C, RP-A, and E. coli SSB were described in detail in our previous publications (Podust et al, 1992a,b). BPV1 El protein was overexpressed in E. coli and purified as described (Muller et al, 1994). SV40 Tag was kindly provided by J. Sogo (Zurich).…”

Section: Methodsmentioning

confidence: 99%

DNA polymerase .delta. holoenzyme: action on single-stranded DNA and on double-stranded DNA in the presence of replicative DNA helicases

Podust

Podust²,

Müller³

et al. 1995

Biochemistry

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DNA polymerase delta requires proliferating cell nuclear antigen and replication factor C to form a holoenzyme efficient in DNA synthesis. We have analyzed three different aspects of calf thymus DNA polymerase delta holoenzyme: (i) analysis of pausing during DNA synthesis, (ii) replication of double-stranded DNA in the absence of additional factors, and (iii) replication of double-stranded DNA in the presence of the two known replicative DNA helicases from simian virus 40 and bovine papilloma virus. DNA polymerase delta holoenzyme replicated primed single-stranded DNA at a rate of 100-300 nucleotides/min, partially overcoming multiple pause sites on DNA. While Escherichia coli single-strand DNA binding protein helped DNA polymerase delta pass through pause sites, the DNA polymerase delta itself appeared to dissociate from the template in the absence of synthesis or when encountering pause sites. Proliferating cell nuclear antigen likely remained on the template. DNA polymerase delta holoenzyme could perform limited strand displacement synthesis on double-stranded gapped circular DNA, and this reaction was not stimulated either by replication protein A or by E. coli single-strand DNA binding protein. DNA polymerase delta holoenzyme could efficiently cooperate with replicative DNA helicases from simian virus 40 (large T antigen) and bovine papilloma virus 1 (protein E1) in replication through double-stranded DNA in a reaction that required replication protein A or E. coli single-strand DNA binding protein.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Methodsmentioning

confidence: 99%

DNA polymerase .delta. holoenzyme: action on single-stranded DNA and on double-stranded DNA in the presence of replicative DNA helicases

Podust

Podust²,

Müller³

et al. 1995

Biochemistry

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“…There is evidence of E1 affecting the function of RPA and of E1 potentially acting to load RPA onto ssDNA being extruded from the E1 helicase [52]. Although there is no direct evidence of this interaction being essential for HPV DNA replication, it is known that Escherichia coli single-stranded DNA binding protein cannot replace RPA for ssDNA binding function in the DNA replication of many small DNA viruses, including PVs [54,[91][92][93], implying that a specific interaction is required between E1 and RPA. Whether this specificity is at the level of RPA loading onto ssDNA or at the level of primer synthesis with the E1-RPA interaction playing a role in primer synthesis, as has been shown for the SV40 Tag-RPA interaction [54], is currently unknown.…”

Section: Replication Protein a Interactionmentioning

confidence: 99%

Targeting Human Papillomavirus Genome Replication for Antiviral Drug Discovery

Archambault

Melendy

2013

Antiviral Therapy

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Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein–protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics.

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“…Conversely, viral DNA replication and helicase phosphorylation of a very similar viral DNA replication system, HPV16, which relies on many of the same host DNA replication proteins as SV40 (38,39), were both unaffected by ETO treatment (13). These findings suggested that ATR/ATM phosphorylation of LT could play a unique role in the inhibition of SV40 DNA replication.…”

Section: Introductionmentioning

confidence: 97%

“…Treatment of SV40 LT-expressing HEK293T cells with etoposide (ETO), a chemotherapeutic agent that inhibits cellular topoisomerase II and causes dsDNA breaks (DSBs), leads to dramatic inhibition of SV40 DNA replication through trans-acting mechanisms, and increased phosphorylation of LT by human DDR kinases ATR/ATM on one or more SQ/TQ sites (13). Conversely, viral DNA replication and helicase phosphorylation of a very similar viral DNA replication system, HPV16, which relies on many of the same host DNA replication proteins as SV40 (38,39), were both unaffected by ETO treatment (13). These findings suggested that ATR/ATM phosphorylation of LT could play a unique role in the inhibition of SV40 DNA replication.…”

Section: Introductionmentioning

confidence: 99%

DNA damaged-induced phosphorylation of a viral replicative DNA helicase results in inhibition of DNA replication through attenuation of helicase function

Homiski,

Dey-Rao,

Shen

et al. 2023

Preprint

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A major function of the DNA damage responses (DDRs) that act during the replicative phase of the cell cycle is to inhibit initiation and elongation of DNA replication. The polyomavirus SV40 is an important model system for studying human DNA replication and DDRs due to its heavy reliance on host factors for viral DNA replication, and the arrest of SV40 DNA replication in response to DDR activation. The inhibition of SV40 DNA replication following DDR activation is associated with enhanced DDR kinase phosphorylation of SV40 Large T-antigen (LT), the viral origin-binding protein and DNA helicase. NetPhos prediction of LT phosphorylation on multiple sites were confirmed by mass spectroscopy, including a highly conserved DDR kinase site, T518. In cell-based DNA replication assays expression of the phosphomimetic mutant form of LT at T518 (T518D) resulted in dramatically decreased levels of SV40 DNA replication; while LT-dependent transcriptional activation was unaffected. WT and LT T518D were subsequently expressed, purified, and analyzedin vitrofor assessment of biochemical function. In concordance with the cell-based data, reactions using SV40 LT-T518D, but not T518A, showed dramatic inhibition of SV40 DNA replication. Importantly, the LT T518D mutation did not affect critical LT protein interactions or its ATPase function, but showed decreased helicase activity on long, but not very short, DNA templates. These results suggest that DDR phosphorylation at T518 inhibits SV40 DNA replication by impeding LT helicase activity, thereby slowing the DNA replication fork. This is consistent with the slowing of cellular replication forks following DDR and may provide a paradigm for another mechanism for how DNA replication forks can be slowed in response to DDR, by phosphorylation of DNA helicases.

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Replication of bovine papillomavirus type 1 origin-containing DNA in crude extracts and with purified proteins.

Cited by 61 publications

References 49 publications

DNA polymerase .delta. holoenzyme: action on single-stranded DNA and on double-stranded DNA in the presence of replicative DNA helicases

DNA polymerase .delta. holoenzyme: action on single-stranded DNA and on double-stranded DNA in the presence of replicative DNA helicases

Targeting Human Papillomavirus Genome Replication for Antiviral Drug Discovery

DNA damaged-induced phosphorylation of a viral replicative DNA helicase results in inhibition of DNA replication through attenuation of helicase function

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