دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination.
المؤلفون: Zhao H; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States., Hartono SR; Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States., de Vera KMF; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States., Yu Z; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States.; Graduate Group in Biostatistics, University of California, Davis, Davis, United States., Satchi K; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States., Zhao T; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States., Sciammas R; Center for Immunology and Infectious Diseases, University of California, Davis, Davis, United States., Sanz L; Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States., Chédin F; Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States., Barlow J; Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, United States.
المصدر: ELife [Elife] 2022 Dec 21; Vol. 11. Date of Electronic Publication: 2022 Dec 21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Ribonucleases*/genetics , Recombination, Genetic*, Humans ; Immunoglobulin Class Switching/genetics ; Endoribonucleases/genetics ; Immunoglobulin Isotypes/genetics ; Genomic Instability ; Cytidine Deaminase/genetics
مستخلص: 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.
Competing Interests: HZ, SH, Kd, ZY, KS, TZ, RS, LS, FC, JB No competing interests declared
(© 2022, Zhao et al.)
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معلومات مُعتمدة: R35 GM139549 United States GM NIGMS NIH HHS; R21 AI151610 United States AI NIAID NIH HHS; K22 CA188106 United States CA NCI NIH HHS; R01 GM134537 United States GM NIGMS NIH HHS; S10 OD010786 United States OD NIH HHS; S10 OD018223 United States OD NIH HHS; P30 CA093373 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: DNA repair; R loops; chromosomes; class switch recombination; gene expression; immunology; inflammation; mouse
Local Abstract: [plain-language-summary] The immune system is a complex network of cells and molecules, which helps to protect the body from invaders. The adaptive immune system can recognise millions of assailants, kill them, and ‘learn’ from this experience to mount an even quicker defence the next time the body is infected. To achieve this level of protection, specific immune cells, called B cells, divide when they come into contact with a molecule from a foreign particle, the antigen. The cloned B cells then produce millions of protective proteins, the antibodies, which patrol the blood stream and tag harmful particles for destruction. An antibody resembles a Y-shaped structure that contains a ‘variable’ region, which gives it the specificity to interact with an antigen, and a ‘constant’ region, which interacts with components of the immune system and determines the mechanisms used to destroy a pathogen. Based on the constant region, antibodies can be divided into five main classes. B cells are able to switch their production from one antibody class to another in an event known as class switch recombination, by making changes to the constant region. They do this by cutting out a portion of the genes for the constant region from their DNA and fusing the remaining DNA. The resulting antibodies still recognise the same target, but interact with different components of the immune system, ensuring that all the body’s forces are mobilised. R-loops are temporary structures that form when a cell ‘reads’ the instructions in its DNA to make proteins. R-loops provide physical support by anchoring the transcription template to the DNA. They help control the activity of genes, but if they stay on the DNA for too long they could interfere with any form of. DNA repair – including the cutting and fusing mechanisms during class switch recombination. To find out more about this process, Zhao et al. used B-cells from mice lacking two specific proteins that usually help to remove R-loops. Without these proteins, the B cells generated more R-loops than normal. Nevertheless, the B-cells were able to undergo class switch recombination, even though their chromosomes showed large areas of DNA damage, and DNA sections that had been repaired contained several mistakes. Errors that occur during class switch recombination have been linked to immune disorders and B cell cancers. The study of Zhao et al. shows that even if R-loops do not affect some processes in B cells, they could still impact the overall health of their DNA. A next step would be to test if an inability to remove R-loops could indeed play a role in immune disorders and B-cell cancers.
سلسلة جزيئية: GEO GSE201210
المشرفين على المادة: EC 3.1.- (Ribonucleases)
EC 3.1.- (Endoribonucleases)
0 (Immunoglobulin Isotypes)
EC 3.5.4.5 (Cytidine Deaminase)
تواريخ الأحداث: Date Created: 20221221 Date Completed: 20221223 Latest Revision: 20230706
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9771370
DOI: 10.7554/eLife.78917
PMID: 36542058
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.78917