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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kanehiro, Yuichi Negishi, Misaki Takemoto, Masayuki Fukuoka, Junji Li, Xialu Todo, Kagefumi Manley, James L. Kanayama, Naoki Hikasa, Takuya Magari, Masaki Ohmori, Hitoshi Kaga, Yoshiaki Gan, Wenjian |
| Description | Author Affiliation: Kanehiro Y ( Department of Bioscience and Biotechnology, Okayama University Graduate School of Natural Science and Technology, Tsushima-Naka, Kita-Ku, Okayama 700-8530, Japan.); |
| Abstract | 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cytidine Deaminase Metabolism Nuclear Proteins RNA-Binding Proteins Somatic Hypermutation, Immunoglobulin Immunology Animals B-Lymphocytes Blotting, Western Chromatin Immunoprecipitation DNA Primers Genetics DNA, Complementary Biosynthesis Mice NIH 3T3 Cells Protein Isoforms RNA Isolation & Purification Reverse Transcriptase Polymerase Chain Reaction Serine-Arginine Splicing Factors Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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