The ATM kinase restrains joining of both VDJ signal and coding ends1

• Published in: The Journal of immunology (1950) Vol. 197; no. 8; pp. 3165 - 3174
• Main Authors: Meek, Katheryn, Xu, Yao, Bailie, Caleb, Yu, Kefei, Neal, Jessica A.
• Format: Journal Article
• Language: English
• Published: 29.08.2016
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600597

The evidence that ATM affects resolution of RAG induced DNA double strand breaks (DSBs) is profuse and unequivocal; moreover, it is clear that the RAG complex itself cooperates (in an undetermined way) with ATM to facilitate repair of these DSBs by the classical non-homologous end joining pathway (c-NHEJ). The mechanistic basis for the cooperation between ATM and the RAG complex has not been defined, although proposed models invoke ATM and RAG2’s C-terminus in maintaining the RAG post-cleavage complex (PCC). Here we show that ATM reduces the rate of both coding and signal joining in a robust episomal assay; we suggest that this is the result of increased stability of the PCC. ATM’s ability to inhibit VDJ joining requires its enzymatic activity. The “non-core” C-termini of both RAG1 and RAG2 are also required for ATM’s capacity to limit signal (but not coding) joining. Moreover, potential phosphorylation targets within the C-terminus of RAG2 are also required for ATM’s capacity to limit signal joining. These data suggest a model whereby the RAG signal end complex is stabilized by phosphorylation of RAG2 by ATM.