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

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

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The 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.

Original languageEnglish (US)
Pages (from-to)1721-1734
Number of pages14
JournalNature Genetics
Volume55
Issue number10
DOIs
StatePublished - Oct 2023

ASJC Scopus subject areas

  • Genetics

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