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E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells
Programmed mutagenesis of the immunoglobulin locus of B lymphocytes during class switch recombination (CSR) and somatic hypermutation requires RNA polymerase II (polII) transcription complex-dependent targeting of the DNA mutator activation-induced cytidine deaminase (AID). AID deaminates cytidine r...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759698/ https://www.ncbi.nlm.nih.gov/pubmed/23964096 http://dx.doi.org/10.1101/gad.210211.112 |
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author | Sun, Jianbo Keim, Celia D. Wang, Jiguang Kazadi, David Oliver, Paula M. Rabadan, Raul Basu, Uttiya |
author_facet | Sun, Jianbo Keim, Celia D. Wang, Jiguang Kazadi, David Oliver, Paula M. Rabadan, Raul Basu, Uttiya |
author_sort | Sun, Jianbo |
collection | PubMed |
description | Programmed mutagenesis of the immunoglobulin locus of B lymphocytes during class switch recombination (CSR) and somatic hypermutation requires RNA polymerase II (polII) transcription complex-dependent targeting of the DNA mutator activation-induced cytidine deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism, and this activity is stimulated by the RNA polII stalling cofactor Spt5 and the 11-subunit cellular noncoding RNA 3′–5′ exonucleolytic processing complex RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event, leading to generation of 3′ end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. We found that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes and defective CSR. Taken together, our study links noncoding RNA processing following RNA polII pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of noncoding RNAs that are generated by stalled RNA polII genome-wide. |
format | Online Article Text |
id | pubmed-3759698 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-37596982014-02-15 E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells Sun, Jianbo Keim, Celia D. Wang, Jiguang Kazadi, David Oliver, Paula M. Rabadan, Raul Basu, Uttiya Genes Dev Research Paper Programmed mutagenesis of the immunoglobulin locus of B lymphocytes during class switch recombination (CSR) and somatic hypermutation requires RNA polymerase II (polII) transcription complex-dependent targeting of the DNA mutator activation-induced cytidine deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism, and this activity is stimulated by the RNA polII stalling cofactor Spt5 and the 11-subunit cellular noncoding RNA 3′–5′ exonucleolytic processing complex RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event, leading to generation of 3′ end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. We found that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes and defective CSR. Taken together, our study links noncoding RNA processing following RNA polII pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of noncoding RNAs that are generated by stalled RNA polII genome-wide. Cold Spring Harbor Laboratory Press 2013-08-15 /pmc/articles/PMC3759698/ /pubmed/23964096 http://dx.doi.org/10.1101/gad.210211.112 Text en © 2013, Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/3.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/. |
spellingShingle | Research Paper Sun, Jianbo Keim, Celia D. Wang, Jiguang Kazadi, David Oliver, Paula M. Rabadan, Raul Basu, Uttiya E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title | E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title_full | E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title_fullStr | E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title_full_unstemmed | E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title_short | E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells |
title_sort | e3-ubiquitin ligase nedd4 determines the fate of aid-associated rna polymerase ii in b cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759698/ https://www.ncbi.nlm.nih.gov/pubmed/23964096 http://dx.doi.org/10.1101/gad.210211.112 |
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