Publication Date:
2014-08-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372240/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372240/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pefanis, Evangelos -- Wang, Jiguang -- Rothschild, Gerson -- Lim, Junghyun -- Chao, Jaime -- Rabadan, Raul -- Economides, Aris N -- Basu, Uttiya -- 1DP2OD008651-01/OD/NIH HHS/ -- 1R01AI099195-01A1/AI/NIAID NIH HHS/ -- 1R01CA179044-01A1/CA/NCI NIH HHS/ -- 1R01CA185486-01/CA/NCI NIH HHS/ -- 1U54CA121852-05/CA/NCI NIH HHS/ -- DP2 OD008651/OD/NIH HHS/ -- R01 AI099195/AI/NIAID NIH HHS/ -- U54 CA121852/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 16;514(7522):389-93. doi: 10.1038/nature13580. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA [2] Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA [3]. ; 1] Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Systems Biology and Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA [3]. ; 1] Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA [2]. ; Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Systems Biology and Department of Biomedical Informatics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Regeneron Pharmaceuticals, Tarrytown, New York 10591, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119026" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
B-Lymphocytes/*metabolism
;
Base Pairing
;
Cytidine Deaminase/*metabolism
;
DNA Breaks, Double-Stranded
;
DNA, Single-Stranded/chemistry/genetics/metabolism
;
Exosome Multienzyme Ribonuclease Complex/deficiency/genetics
;
Exosomes/metabolism
;
Female
;
Genome/genetics
;
Genomic Instability/genetics
;
Immunoglobulin Class Switching/genetics
;
Immunoglobulin Heavy Chains/genetics
;
Male
;
Mice
;
Nucleic Acid Hybridization
;
RNA, Antisense/biosynthesis/chemistry/genetics/metabolism
;
RNA, Untranslated/*biosynthesis/chemistry/*genetics/metabolism
;
RNA-Binding Proteins/genetics
;
Somatic Hypermutation, Immunoglobulin/genetics
;
Substrate Specificity
;
Transcription Initiation Site
;
Transcription, Genetic/*genetics
;
Translocation, Genetic/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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