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タイトル: | C-terminal region of activation-induced cytidine deaminase (AID) is required for efficient class switch recombination and gene conversion. |
著者: | Sabouri, Somayeh Kobayashi, Maki Begum, Nasim A Xu, Jianliang Hirota, Kouji Honjo, Tasuku |
著者名の別形: | 本庶, 佑 |
キーワード: | DNA repair CSR synapse |
発行日: | 11-Feb-2014 |
出版者: | National Academy of Sciences |
誌名: | Proceedings of the National Academy of Sciences of the United States of America |
巻: | 111 |
号: | 6 |
開始ページ: | 2253 |
終了ページ: | 2258 |
抄録: | Activation-induced cytidine deaminase (AID) introduces single-strand breaks (SSBs) to initiate class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM). CSR is mediated by double-strand breaks (DSBs) at donor and acceptor switch (S) regions, followed by pairing of DSB ends in two S regions and their joining. Because AID mutations at its C-terminal region drastically impair CSR but retain its DNA cleavage and SHM activity, the C-terminal region of AID likely is required for the recombination step after the DNA cleavage. To test this hypothesis, we analyzed the recombination junctions generated by AID C-terminal mutants and found that 0- to 3-bp microhomology junctions are relatively less abundant, possibly reflecting the defects of the classical nonhomologous end joining (C-NHEJ). Consistently, the accumulation of C-NHEJ factors such as Ku80 and XRCC4 was decreased at the cleaved S region. In contrast, an SSB-binding protein, poly (ADP)-ribose polymerase1, was recruited more abundantly, suggesting a defect in conversion from SSB to DSB. In addition, recruitment of critical DNA synapse factors such as 53BP1, DNA PKcs, and UNG at the S region was reduced during CSR. Furthermore, the chromosome conformation capture assay revealed that DNA synapse formation is impaired drastically in the AID C-terminal mutants. Interestingly, these mutants showed relative reduction in GC compared with SHM in chicken DT40 cells. Collectively, our data indicate that the C-terminal region of AID is required for efficient generation of DSB in CSR and GC and thus for the subsequent pairing of cleaved DNA ends during recombination in CSR. |
著作権等: | © 2014 National Academy of Sciences. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/183988 |
DOI(出版社版): | 10.1073/pnas.1324057111 |
PubMed ID: | 24469810 |
出現コレクション: | 学術雑誌掲載論文等 |
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