DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination
Year: 2020
Type: article
Abstract: The DNA-dependent protein kinase (DNA-PK), composed of the KU heterodimer and the large catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with different isotypes by joining two DNA double-strand breaks at different switching regions via the cNHEJ pathway. DNA-PK and the cNHEJ pathway play important roles in the DNA repair phase of CSR. To initiate cNHEJ, KU binds to DNA ends, and recruits and activates DNA-PK. DNA-PKcs is the best-characterized substrate of DNA-PK, which phosphorylates DNA-PKcs at both the S2056 and T2609 clusters. Loss of T2609 cluster phosphorylation increases radiation sensitivity, suggesting a role of T2609 phosphorylation in DNA repair. Using the DNA-PKcs 5A mouse model carrying an alanine substitution at the T2609 cluster, here we show that loss of T2609 phosphorylation of DNA-PKcs does not affect the CSR efficiency. Yet, the CSR junctions recovered from DNA-PKcs 5A/5A B cells reveal increased chromosomal translocation, excess end-resection, and preferential usage of micro-homology – all signs of the alternative end-joining pathway. Thus, these results uncover a role of DNA-PKcs T2609 phosphorylation in promoting cNHEJ repair pathway choice during CSR. Key points Loss of T2069 cluster phosphorylation of DNA-PKcs promotes Alt-EJ-mediated CSR.
Authors: Jennifer L. Crowe, Xiaobin S. Wang, Zhengping Shao, Brian J. Lee, Verna M. Estes, Shan Zha
Institution: Columbia University
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: DNA-PKCS Phosphorylation in DNA Repair and Chromosomal Translocations, DNA double-strand break repair, chromosome translocations and cancer, Non-catalytic functions of DNA-PK in DNA repair and tumorigenesis, The catalytic and non-catalytic functions of PARP1 in cancer biology, Clinical and Translational Science Award, The structural function of ATR in development, oncogenesis and cancer therapy, The role of ATM in the suppression of lymphoid malignancy, NRSA Training Core, Cancer Center Support Grant
OpenAlex ID: W3081551588