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Noncoding RNA transcription targets AID to divergently transcribed loci in B cells
Open accessAbstract
The vast majority of the mammalian genome has the potential to express noncoding RNA (ncRNA). The 11-subunit RNA exosome complex is the main source of cellular 3'-5' exoribonucleolytic activity and potentially regulates the mammalian noncoding transcriptome. Here we generated a mouse model in which the essential subunit Exosc3 of the RNA exosome complex can be conditionally deleted. Exosc3-deficient B cells lack the ability to undergo normal levels of class switch recombination and somatic hypermutation, two mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein activation-induced cytidine deaminase (AID). The transcriptome of Exosc3-deficient B cells has revealed the presence of many novel RNA exosome substrate ncRNAs. RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 base pairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are frequent translocation partners of DNA double-strand breaks generated at Igh in B cells. Strikingly, translocations near TSSs or within gene bodies occur over regions of RNA exosome substrate ncRNA expression. These RNA exosome-regulated, antisense-transcribed regions of the B-cell genome recruit AID and accumulate single-strand DNA structures containing RNA-DNA hybrids. We propose that RNA exosome regulation of ncRNA recruits AID to single-strand DNA-forming sites of antisense and divergent transcription in the B-cell genome, thereby creating a link between ncRNA transcription and overall maintenance of B-cell genomic integrity.
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“Pathogenic variants in EXOSC3, a noncatalytic subunit of the RNA exosome, cause pontocerebellar hypoplasia type 1B (PCH1B)”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]
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“PCH1B is a subtype characterized by marked hypotonia, progressive cerebellar atrophy, and motor neuron dysfunction and caused by variants in the EXOSC3 gene15,18,21–23,25.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“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.”
From EXOSC3 G191 Variants Trigger System-Wide Recalibration of RNA Processing Machinery (2026) · cites this paper as [22]
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Metadata
- Authors
- Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A. N., & Basu, U.
- Affiliations
- Columbia University (US)
- Regeneron (United States) (US)
- Corresponding author
- Basu, Uttiya
- Venue
- Nature
- Published
- 2014-08-06
- Volume
- 514
- Issue
- 7522
- Pages
- 389-393
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4372240
- OpenAlex
- W1987152324
- Cited by
- 201
- References
- 40
- Citations by year
- 2026: 19 · 2025: 12 · 2024: 15 · 2023: 17 · 2022: 14 · 2021: 15 · 2020: 14 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 22 · 2015: 19 · 2014: 6
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (1dp2od008651-01)
- National Cancer Institute (U54CA121852, R01CA185486, R01CA179044)
- National Institute of Allergy and Infectious Diseases (R01AI099195)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- RNA exosome, EXOSC3, activation-induced cytidine deaminase, AID, non-coding RNA, antisense transcription, divergent transcription, class switch recombination, somatic hypermutation, R-loops, genomic instability, chromosomal translocation, B cells, conditional knockout mice, transcription start sites, antibody diversity, 3'-5' exoribonuclease
- MeSH terms
- AICDA (Activation-Induced Cytidine Deaminase), Animals, B-Lymphocytes, Cytidine Deaminase, DNA, Single-Stranded, Female, Immunoglobulin Heavy Chains, Male, Nucleic Acid Hybridization, Substrate Specificity, Transcription, Genetic, Translocation, Genetic, RNA, Antisense, RNA-Binding Proteins, Genome, Immunoglobulin Class Switching, Base Pairing, RNA, Untranslated, Transcription Initiation Site, Somatic Hypermutation, Immunoglobulin, Genomic Instability, Mice, DNA Breaks, Double-Stranded, Exosomes, Exosome Multienzyme Ribonuclease Complex
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