期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：34
页码：8615-8620
DOI：10.1073/pnas.1808490115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a classical nonhomologous end-joining (cNHEJ) factor. Loss of DNA-PKcs diminished mature B cell class switch recombination (CSR) to other isotypes, but not IgG1. Here, we show that expression of the kinase-dead DNA-PKcs ( DNA-PKcs KD / KD ) severely compromises CSR to IgG1. High-throughput sequencing analyses of CSR junctions reveal frequent accumulation of nonproductive interchromosomal translocations, inversions, and extensive end resection in DNA-PKcs KD / KD , but not DNA-PKcs −/− , B cells. Meanwhile, the residual joints from DNA-PKcs KD/KD cells and the efficient Sµ-Sγ1 junctions from DNA-PKcs −/− B cells both display similar preferences for small (2–6 nt) microhomologies (MH). In DNA-PKcs −/− cells, Sµ-Sγ1 joints are more resistant to inversions and extensive resection than Sµ-Sε and Sµ-Sµ joints, providing a mechanism for the isotype-specific CSR defects. Together, our findings identify a kinase-dependent role of DNA-PKcs in suppressing MH-mediated end joining and a structural role of DNA-PKcs protein in the orientation of CSR.
关键词：DNA-PKcs ; immunoglobulin class switch recombination ; classical nonhomologous end joining ; alternative end joining ; somatic mutation
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