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| Status |
Public on Dec 14, 2022 |
| Title |
Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Class switch recombination generates antibody distinct isotypes critical to a robust adaptive immune system and defects are associated with auto-immune disorders and lymphomagenesis. Transcription is required during class switch to recruit the cytidine deaminase AID—an essential step for the formation of DNA doublestrand 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 class switch recombination efficiency, transcriptional activity, or AID recruitment. 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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| Overall design |
Using LAMS-HTGTS and DRIP-seq to characterize translocation/mutation profile and R-loop formation at IgH region during class switch recombination in mouse B-cells which lack R-loop removal enzymes (setx-/-, rnaseh2b-/-, and setx-/- rnaseh2b-/-).
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| Contributor(s) |
Zhao H, Hartono S, De Vera K, Yu Z, Satchi K, Zhao T, Sciammas R, Sanz L, Chedin F, Barlow J |
| Citation(s) |
36542058 |
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| Submission date |
Apr 21, 2022 |
| Last update date |
Jan 11, 2023 |
| Contact name |
Frederic Chedin |
| E-mail(s) |
flchedin@ucdavis.edu
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| Organization name |
UC Davis
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| Department |
MCB
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| Lab |
Chedin
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| Street address |
1 Shields Avenue
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| City |
Davis |
| State/province |
CA |
| ZIP/Postal code |
95616 |
| Country |
USA |
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| Platforms (2) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (24)
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| GSM6052729 |
LAMS HTGTS-seq rnaseh2b-/- setx-/- biol rep 1 |
| GSM6052730 |
LAMS HTGTS-seq rnaseh2b-/- biol rep 1 |
| GSM6052731 |
LAMS HTGTS-seq setx-/- biol rep 1 |
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| Relations |
| BioProject |
PRJNA830361 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE201210_RAW.tar |
1.7 Gb |
(http)(custom) |
TAR (of BIGBED, BIGWIG, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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