| Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1. | |
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MedLine Citation:
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PMID: 22232677 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID-induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM. |
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Authors:
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Yuichi Kanehiro; Kagefumi Todo; Misaki Negishi; Junji Fukuoka; Wenjian Gan; Takuya Hikasa; Yoshiaki Kaga; Masayuki Takemoto; Masaki Magari; Xialu Li; James L Manley; Hitoshi Ohmori; Naoki Kanayama |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-9 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: - ISSN: 1091-6490 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Bioscience and Biotechnology, Okayama University Graduate School of Natural Science and Technology, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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