| First Author | Crowe JL | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 34 | Pages | 8615-8620 |
| PubMed ID | 30072430 | Mgi Jnum | J:264598 |
| Mgi Id | MGI:6196934 | Doi | 10.1073/pnas.1808490115 |
| Citation | Crowe JL, et al. (2018) Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination. Proc Natl Acad Sci U S A 115(34):8615-8620 |
| abstractText | 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 Smicro-Sgamma1 junctions from DNA-PKcs(-/-) B cells both display similar preferences for small (2-6 nt) microhomologies (MH). In DNA-PKcs(-/-) cells, Smicro-Sgamma1 joints are more resistant to inversions and extensive resection than Smicro-Sepsilon and Smicro-Smicro 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. |
