1Restoration of ATM expression in DNA-PKcs deficient cells inhibits signal end joining

• Published in: The Journal of immunology (1950) Vol. 196; no. 7; pp. 3032 - 3042
• Main Authors: Neal, Jessica A., Xu, Yao, Abe, Masumi, Hendrickson, Eric, Meek, Katheryn
• Format: Journal Article
• Language: English
• Published: 26.02.2016
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1501654

Unlike most DNA-PKcs deficient mouse cell strains, we show here that targeted deletion of DNA-PKcs in two different human cell lines abrogates VDJ signal end joining in episomal assays. Although the mechanism is not well defined, DNA-PKcs deficiency results in spontaneous reduction of ATM expression in many cultured cell lines (including those studied here) and in DNA-PKcs deficient mice. We considered that varying loss of ATM expression might explain differences in signal end joining in different cell strains and animal models, and we investigated the impact of ATM and/or DNA-PKcs loss on VDJ recombination in cultured human and rodent cell strains. To our surprise, in DNA-PKcs deficient mouse cell strains that are proficient in signal end joining, restoration of ATM expression markedly inhibits signal end joining. In contrast, in DNA-PKcs deficient cells that are deficient in signal end joining, complete loss of ATM enhances signal (but not coding) joint formation. We propose that ATM facilitates restriction of signal ends to the “classical” non-homologous end-joining pathway.