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PLoS Genet. 2015 Nov 6;11(11):e1005645. doi: 10.1371/journal.pgen.1005645. eCollection 2015 Nov.

DNA Repair Cofactors ATMIN and NBS1 Are Required to Suppress T Cell Activation.

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CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Division of Immunobiology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Vienna, Austria.
London Research Institute, Cancer Research UK, London, United Kingdom.
Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria.
Clinical Institute for Pathology, Medical University Vienna, Vienna, Austria.


Proper development of the immune system is an intricate process dependent on many factors, including an intact DNA damage response. The DNA double-strand break signaling kinase ATM and its cofactor NBS1 are required during T cell development and for the maintenance of genomic stability. The role of a second ATM cofactor, ATMIN (also known as ASCIZ) in T cells is much less clear, and whether ATMIN and NBS1 function in synergy in T cells is unknown. Here, we investigate the roles of ATMIN and NBS1, either alone or in combination, using murine models. We show loss of NBS1 led to a developmental block at the double-positive stage of T cell development, as well as reduced TCRα recombination, that was unexpectedly neither exacerbated nor alleviated by concomitant loss of ATMIN. In contrast, loss of both ATMIN and NBS1 enhanced DNA damage that drove spontaneous peripheral T cell hyperactivation, proliferation as well as excessive production of proinflammatory cytokines and chemokines, leading to a highly inflammatory environment. Intriguingly, the disease causing T cells were largely proficient for both ATMIN and NBS1. In vivo this resulted in severe intestinal inflammation, colitis and premature death. Our findings reveal a novel model for an intestinal bowel disease phenotype that occurs upon combined loss of the DNA repair cofactors ATMIN and NBS1.

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