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Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination

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 f...

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Autores principales: Zhao, Hongchang, Hartono, Stella R, de Vera, Kirtney Mae Flores, Yu, Zheyuan, Satchi, Krishni, Zhao, Tracy, Sciammas, Roger, Sanz, Lionel, Chédin, Frédéric, Barlow, Jacqueline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771370/
https://www.ncbi.nlm.nih.gov/pubmed/36542058
http://dx.doi.org/10.7554/eLife.78917
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author Zhao, Hongchang
Hartono, Stella R
de Vera, Kirtney Mae Flores
Yu, Zheyuan
Satchi, Krishni
Zhao, Tracy
Sciammas, Roger
Sanz, Lionel
Chédin, Frédéric
Barlow, Jacqueline
author_facet Zhao, Hongchang
Hartono, Stella R
de Vera, Kirtney Mae Flores
Yu, Zheyuan
Satchi, Krishni
Zhao, Tracy
Sciammas, Roger
Sanz, Lionel
Chédin, Frédéric
Barlow, Jacqueline
author_sort Zhao, Hongchang
collection PubMed
description 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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spelling pubmed-97713702022-12-22 Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination Zhao, Hongchang Hartono, Stella R de Vera, Kirtney Mae Flores Yu, Zheyuan Satchi, Krishni Zhao, Tracy Sciammas, Roger Sanz, Lionel Chédin, Frédéric Barlow, Jacqueline eLife Chromosomes and Gene Expression 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. eLife Sciences Publications, Ltd 2022-12-21 /pmc/articles/PMC9771370/ /pubmed/36542058 http://dx.doi.org/10.7554/eLife.78917 Text en © 2022, Zhao et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Chromosomes and Gene Expression
Zhao, Hongchang
Hartono, Stella R
de Vera, Kirtney Mae Flores
Yu, Zheyuan
Satchi, Krishni
Zhao, Tracy
Sciammas, Roger
Sanz, Lionel
Chédin, Frédéric
Barlow, Jacqueline
Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title_full Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title_fullStr Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title_full_unstemmed Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title_short Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
title_sort senataxin and rnase h2 act redundantly to suppress genome instability during class switch recombination
topic Chromosomes and Gene Expression
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771370/
https://www.ncbi.nlm.nih.gov/pubmed/36542058
http://dx.doi.org/10.7554/eLife.78917
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