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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice
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Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice

机译：AID丝氨酸38磷酸化位点的完整性对于小鼠中的类别转换重组和体细胞超突变至关重要

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摘要

Activation-induced cytidine deaminase (AID) is a single-stranded (ss) DNA-specific cytidine deaminase that initiates Ig heavy chain (IgH) class switch recombination (CSR) and Ig somatic hypermutation (SHM) by deaminating cytidines within, respectively, IgH switch (S) regions and Ig variable region (V) exons. AID that is phosphorylated on serine residue 38 interacts with replication protein A (RPA), a ssDNA binding protein, to promote deamination of transcribed double-stranded DNA in vitro, which, along with other evidence, suggests that AID may similarly gain access to transcribed S regions and V exons in vivo. However, the physiological role of AID phosphorylation at serine residue 38 (S38), and even the requirement for the S38 residue, with respect to CSR or SHM has been debated. To address this issue, we used gene targeting to generate an endogenous mouse AID locus that produces AID in which S38 is substituted with alanine (AID~(S38A)), a mutant form of AID that retains similar catalytic activity on ssDNA as WT AID (AID~(WT)). B cells homozygous for the AID~(S38A) mutation show substantially impaired CSR and SHM, correlating with inability of AID~(S38A) to interact with endogenous RPA. Moreover, mice haploinsufficient for AID~(S38A) have even more severely impaired CSR when compared with mice haploinsufficient for AID~(WT), with CSR levels reduced to nearly background levels. These results unequivocally demonstrate that integrity of the AID S38 phosphorylation site is required for normal CSR and SHM in mice and strongly support a role for AID phosphorylation at S38 and RPA interaction in regulating CSR and SHM.
机译：激活诱导的胞苷脱氨酶（AID）是单链（ss）DNA特异性胞苷脱氨酶，可通过分别在IgH中脱氨胞苷来引发Ig重链（IgH）类开关重组（CSR）和Ig体细胞超突变（SHM）。开关（S）区和Ig可变区（V）外显子。在丝氨酸残基38上被磷酸化的AID与ssDNA结合蛋白复制蛋白A（RPA）相互作用，以促进体外转录的双链DNA的脱氨基作用，这与其他证据一起表明，AID可以类似地获得转录的途径。体内的S区和V外显子。但是，关于CSR或SHM，丝氨酸残基38（S38）上AID磷酸化的生理作用，甚至对S38残基的要求，都存在争议。为了解决这个问题，我们使用基因靶向来产生内源性小鼠AID基因座，该基因座产生的AID中的S38被丙氨酸（AID〜（S38A））取代，AID的突变形式在ssDNA上保留了与WT AID相似的催化活性（ AID〜（WT））。 AID_（S38A）突变纯合的B细胞显示出严重的CSR和SHM受损，这与AID_（S38A）无法与内源性RPA相互作用有关。此外，与单倍不足的AID〜（WT）小鼠相比，单倍不足的AID〜（S38A）小鼠的CSR受到更严重的损害，CSR水平降低到接近本底水平。这些结果明确表明，正常CSR和SHM在小鼠中需要AID S38磷酸化位点的完整性，并强烈支持AID S38和RPA相互作用时AID磷酸化在调节CSR和SHM中的作用。

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    Hwei-Ling Cheng; Bao Q. Vuong; Uttiya Basu; Andrew Franklin; Bjoern Schwer; Jillian Astarita; Ryan T. Phan; Abhishek Datta; John Manis; Frederick W. Alt; Jayanta Chaudhuri;

  • 作者单位

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Howard Hughes Medical Institute, The Children's Hospital Department of Genetics, Harvard Medical School, and The Immune Disease Institute,Boston, MA 02115;

    Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    activation-induced deaminase; protein kinase A; R-loop;

    机译：激活诱导的脱氨酶;蛋白激酶A;R环;

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