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Transcription is required during class switch recombination to recruit the cytidine deaminase AID\u2014an essential step for the formation of DNA double-strand breaks\u2014and strongly induces the formation of R loops within the immunoglobulin heavy-chain locus. However, the impact of R loops on double-strand break formation and repair during class switch recombination remains unclear. Here, we report that cells lacking two enzymes involved in R loop removal\u2014senataxin and RNase H2\u2014exhibit increased R loop formation and genome instability at the immunoglobulin heavy-chain locus without impacting its transcriptional activity, AID recruitment, or class switch recombination efficiency. Senataxin and RNase H2-deficient cells also exhibit increased insertion mutations at switch junctions, a hallmark of alternative end joining. Importantly, these phenotypes were not observed in cells lacking senataxin or RNase H2B alone. We propose that senataxin acts redundantly with RNase H2 to mediate timely R loop removal, promoting efficient repair while suppressing AID-dependent genome instability and insertional mutagenesis.<\/jats:p>","DOI":"10.7554\/elife.78917","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T07:15:28Z","timestamp":1669014928000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.78917","source":"Crossref","is-referenced-by-count":18,"title":["Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination"],"prefix":"10.7554","volume":"11","author":[{"given":"Hongchang","family":"Zhao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, University of California, Davis","place":["Davis, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella 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