ArticleJournal of virology2023
The SETD2 Methyltransferase Supports Productive HPV31 Replication through the LEDGF/CtIP/Rad51 Pathway.
Article in Journal of virology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
3 citing papers in PubMed, 4 citations in OpenAlex.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The human papillomavirus (HPV) life cycle takes place in the stratified epithelium, with the productive phase being activated by epithelial differentiation. The HPV genome is histone-associated, and the life cycle is epigenetically regulated, in part, by histone tail modifications that facilitate the recruitment of DNA repair factors that are required for viral replication. We previously showed that the SETD2 methyltransferase facilitates the productive replication of HPV31 through the trimethylation of H3K36 on viral chromatin. SETD2 regulates numerous cellular processes, including DNA repair via homologous recombination (HR) and alternative splicing, through the recruitment of various effectors to histone H3 lysine 36 trimethylation (H3K36me3). We previously demonstrated that the HR factor Rad51 is recruited to HPV31 genomes and is required for productive replication; however, the mechanism of Rad51 recruitment has not been defined. SET domain containing 2 (SETD2) promotes the HR repair of double-strand breaks (DSBs) in actively transcribed genes through the recruitment of carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) to lens epithelium-derived growth factor (LEDGF)-bound H3K36me3, which promotes DNA end resection and thereby allows for the recruitment of Rad51 to damaged sites. In this study, we found that reducing H3K36me3 through the depletion of SETD2 or the overexpression of an H3.3K36M mutant leads to an increase in γH2AX, which is a marker of damage, on viral DNA upon epithelial differentiation. This is coincident with decreased Rad51 binding. Additionally, LEDGF and CtIP are bound to HPV DNA in a SETD2-dependent and H3K36me3-dependent manner, and they are required for productive replication. Furthermore, CtIP depletion increases DNA damage on viral DNA and blocks Rad51 recruitment upon differentiation. Overall, these studies indicate that H3K36me3 enrichment on transcriptionally active viral genes promotes the rapid repair of viral DNA upon differentiation through the LEDGF-CtIP-Rad51 axis.
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Registered trials
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