{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T09:17:59Z","timestamp":1763111879810,"version":"3.45.0"},"reference-count":30,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Marian University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The human papillomavirus (HPV) is a small, non-enveloped virus with a circular double-stranded DNA genome. The HPV genome encodes the E2 activator protein, which is required for viral transcription. R-loops are triple-stranded nucleic acid structures that occur when newly synthesized single-stranded RNA anneals to duplex DNA. These structures form during papillomavirus transcription. We and others have demonstrated that resolution of viral R loops is crucial for HPV episomal maintenance. ZPR1 is a zinc finger protein that can recruit SETX to mammalian R-loops to mediate resolution. E2 binds to and recruits SETX, an R-loop helicase, to the viral promoter. We observed E2 in complex with SETX and ZPR1. However, we found that ZPR1 depletion decreased viral R-loops while enhancing cellular R-loops. ZPR1 depletion also increased SETX binding to the viral promoter. These data suggest that ZPR1 is not required for HPV R-loop resolution, in contrast to what has been observed in mammalian cells. We detected the E2 protein associated with R-loops and found that E2 overexpression increases cell-derived R-loop formation. Analysis of TCGA datasets revealed that ZPR1, but not SETX, mRNA expression is significantly reduced in HPV-positive cervical and head and neck cancers. Together, these findings indicate that while E2 mediates HPV R-loop resolution, it also promotes R-loop accumulation in the host genome, likely through SETX sequestration.<\/jats:p>","DOI":"10.3390\/v17111502","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T09:06:36Z","timestamp":1763111196000},"page":"1502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ZPR1 Is Dispensable for HPV R-Loop Resolution but Regulates Host R-Loop Dynamics"],"prefix":"10.3390","volume":"17","author":[{"given":"Rylann","family":"Moffitt","sequence":"first","affiliation":[{"name":"Tom and Julie Wood College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Brooks","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8104-0703","authenticated-orcid":false,"given":"Elliot J.","family":"Androphy","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marsha","family":"DeSmet","sequence":"additional","affiliation":[{"name":"Tom and Julie Wood College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA"},{"name":"Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.15698\/cst2019.02.175","article-title":"R-loops: Formation, function, and relevance to cell stress","volume":"3","author":"Allison","year":"2019","journal-title":"Cell Stress"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41580-019-0206-3","article-title":"Regulatory R-loops as facilitators of gene expression and genome stability","volume":"21","author":"Niehrs","year":"2020","journal-title":"Nat. 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