APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer

Author:

McCann Jennifer L.ORCID,Cristini AgneseORCID,Law Emily K.ORCID,Lee Seo Yun,Tellier MichaelORCID,Carpenter Michael A.ORCID,Beghè Chiara,Kim Jae Jin,Sanchez AnthonyORCID,Jarvis Matthew C.,Stefanovska BojanaORCID,Temiz Nuri A.ORCID,Bergstrom Erik N.,Salamango Daniel J.,Brown Margaret R.,Murphy ShonaORCID,Alexandrov Ludmil B.ORCID,Miller Kyle M.ORCID,Gromak NataliaORCID,Harris Reuben S.ORCID

Abstract

AbstractThe single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

Cancer Prevention and Research Institute of Texas

Cancer Research UK

U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences

Publisher

Springer Science and Business Media LLC

Subject

Genetics

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