Mechanism of somatic hypermutation at the WA motif by human DNA polymerase n

Zhao Y.; Gregory M.T.; Biertümpfel C.Hua Y.-J.Hanaoka F.Yang W.

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Mechanism of somatic hypermutation at the WA motif by human DNA polymerase n

机译：Mechanism of somatic hypermutation at the WA motif by human DNA polymerase n

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Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase n (Pol n) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol n substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T:dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol n. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol n lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol n can extend the T:G mispair efficiently to complete the mutagenesis.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第20期|8146-8151|共6页
作者
Zhao Y.; Gregory M.T.; Biertümpfel C.Hua Y.-J.Hanaoka F.Yang W.;
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作者单位

Institute of Nuclear-Agricultural Sciences, Zhejiang University, Hangzhou 310029, China;

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States;

Faculty of Science, Gakushuin University, Tokyo 171-8588, Japan;

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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
正文语种英语
中图分类自然科学总论;
关键词
A-to-G transition; Immunoglobulin; P-cation stacking;

Mechanism of somatic hypermutation at the WA motif by human DNA polymerase n

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