Year: 2026
Type: article
Abstract: APOBECs are cytidine deaminases whose levels are increased in cells with high-risk HPV genomes and are responsible for most mutations in HPV associated cancers. APOBEC3B is a nuclear member of this family and is shown to be a positive regulator of HPV replication as well as expression. The proviral effects of A3B found in HPV positive cells contrast with its role as a restriction factor for many other viruses. Studies demonstrated that A3B can bind and regulate the formation of R-loops, which are trimeric nucleic acid structures consisting of an RNA paired with its complementary DNA strand, displacing one of the DNA strands. The present study demonstrates that A3B binds stably to both cellular and viral chromatin at sequences containing high R-loop levels, including the HPV URR and early polyadenylation sites. Importantly, A3B was found to play a critical role in the replication of HPV genomes and in regulating viral expression. Reduction of R-loop levels through overexpression of the R-loop specific RNase, RNase H1, impaired A3B binding to viral genomes as well as at multiple cellular sites. When A3B was depleted, total R-loop levels decreased by ~50%, leading to impaired viral transcription and an increase in the expression of immune genes, such as OASL, IL6, and IRF1. Mapping R-loop formation in A3B depleted cells revealed that A3B regulated a subset of R-loops that form on the transcriptional start (TSS) and termination sites (TTS) of cellular genes, including at the HPV URR. Furthermore, A3B depletion resulted in over a 50% reduction of DNA breaks along with altered expression of DNA damage repair proteins. This study demonstrates that A3B is an inducer of R-loop formation and DNA damage in HPV positive cells, thereby regulating cellular and viral gene expression along with HPV replication.
Source: PLoS Pathogens
Institution: Northwestern University
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Northwestern University, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
Awards: G1067263195, G2757448159, Northwestern University Skin Disease Research Core Center, G8212372636, Renewal: HPV and the DNA Damage Response, The Robert H. Lurie Comprehensive Cancer Center, Uncovering the Roles of DNA-pkcs in Regulating R-loops during HPV Replication, HPV Life Cycle and R-loops
OpenAlex ID: W7140124798