Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination.

Abstract:

: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-PKcsKD/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-PKcsKD/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.

authors

Crowe JL,Shao Z,Wang XS,Wei PC,Jiang W,Lee BJ,Estes VM,Alt FW,Zha S

doi

10.1073/pnas.1808490115

subject

Has Abstract

pub_date

2018-08-21 00:00:00

pages

8615-8620

issue

34

eissn

0027-8424

issn

1091-6490

pii

1808490115

journal_volume

115

pub_type

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