Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
Hongchang Zhao,
Stella R Hartono,
Kirtney Mae Flores de Vera,
Zheyuan Yu,
Krishni Satchi,
Tracy Zhao,
Roger Sciammas,
Lionel Sanz,
Frédéric Chédin,
Jacqueline Barlow
Affiliations
Hongchang Zhao
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States
Stella R Hartono
Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
Kirtney Mae Flores de Vera
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States
Zheyuan Yu
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States; Graduate Group in Biostatistics, University of California, Davis, Davis, United States
Krishni Satchi
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States
Tracy Zhao
Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States
Roger Sciammas
Center for Immunology and Infectious Diseases, University of California, Davis, Davis, United States
Lionel Sanz
Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
Frédéric Chédin
Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States
Class switch recombination generates distinct antibody isotypes critical to a robust adaptive immune system, and defects are associated with autoimmune disorders and lymphomagenesis. Transcription is required during class switch recombination to recruit the cytidine deaminase AID—an essential step for the formation of DNA double-strand breaks—and 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—senataxin and RNase H2—exhibit 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.
