Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
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Abstract
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.
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RNAse H2 acts redundantly with the RNA-DNA helicase Senataxin, which recruits the RNA exosome to the genome through a direct interaction with EXOSC9.
“Interestingly, RNAse H2 has been shown to act redundantly with the RNA-DNA helicase Senataxin, which recruits the RNA exosome to the genome through a direct interaction with EXOSC9105,106.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [105]
The Introduction and Discussion report that SETX and RNase H2 cooperate to remove switch-region R loops in B cells, supporting the redundancy claim in that setting. The Discussion mentions the RNA exosome as another factor that can remove these structures, but our copy does not say that senataxin recruits it to the genome or interacts directly with EXOSC9 (no page numbers are provided). (LLM, conf=0.88)
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Senataxin and R-loops homeostasis: multifaced implications in carcinogenesis
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Emerging roles of RNA‐binding proteins in fatty liver disease
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Isolation and Analysis of B-cell Progenitors from Bone Marrow by Flow Cytometry
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EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery
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“Of particular relevance to our work, variants in genes encoding several subunits of the RNA exosome complex have been linked to PCH, including EXOSC3 (PCH1B), EXOSC8 (PCH1C), EXOSC9 (PCH1D), and provisionally EXOSC1 (PCH1F) 15-25 .”
Variability in R-loops levels based on IHC detectionPreprint
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Senataxin promotes recombination fidelity during antigen receptor gene diversification
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Senataxin loss induces cGAS–STING-mediated mitochondrial dysfunctionPreprint
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Self-citation
- Authors
- Zhao, H., Hartono, S. R., de Vera, K. M. F., Yu, Z., Satchi, K., Zhao, T., Sciammas, R., Sanz, L., Chédin, F., & Barlow, J.
- Affiliations
- University of California, Davis (US)
- Department of Microbiology and Molecular Genetics, University of California, Davis
- Department of Molecular and Cellular Biology, University of California, Davis
- Corresponding author
- Barlow, Jacqueline
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-12-21
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9771370
- OpenAlex
- W4312018170
- Cited by
- 18
- References
- 124
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 5 · 2023: 4 · 2022: 1
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (CA188106)
- National Institute of General Medical Sciences (GM134537, GM139549)
- National Institute of Allergy and Infectious Diseases (AI151610)
- University of California Cancer Research Coordinating Committee (Seed Grant CRR-20-635379)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SETX, RNase H2, class switch recombination, genomic instability, R-loops, immunoglobulin heavy chain locus, AID, alternative end-joining, DNA double-strand break repair, antibody isotype switching, lymphomagenesis
- MeSH terms
- Cytidine Deaminase, Endoribonucleases, Humans, Immunoglobulin Isotypes, Recombination, Genetic, Ribonucleases, Immunoglobulin Class Switching, Genomic Instability
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