ATM: Translating the DNA Damage Response to Adaptive Immunity

• Published in: Trends in immunology 2021-04, Vol.42 (4), p.350-365
• Main Authors: Weitering, Thomas J., Takada, Sanami, Weemaes, Corry M.R., van Schouwenburg, Pauline A., van der Burg, Mirjam
• Format: Article
• Language: English
• Subjects: Adaptive control; Adaptive immunity; Antibodies; antibody deficiency; Apoptosis; Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; ATM; Binding sites; Cell cycle; class switch recombination; Class switching; Deoxyribonucleic acid; DNA; DNA damage; DNA double strand break response; DNA repair; Double-strand break repair; Gene loci; Immunodeficiency; Immunoglobulins; Immunology; Kinases; Lung diseases; Lymphocytes; Mutation; Proteins; Recombination; Repair; T cell receptors; V(D)J recombination
• ISSN: 1471-4906; 1471-4981
• DOI: 10.1016/j.it.2021.02.001

ATM is often dubbed the master regulator of the DNA double stranded break (DSB) response. Since proper induction and repair of DNA DSBs forms the core of immunological diversity, it is surprising that patients with ataxia telangiectasia generally have a mild immunodeficiency in contrast to other DSB repair syndromes. In this review, we address this discrepancy by delving into the functions of ATM in DSB repair and cell cycle control and translate these to adaptive immunity. We conclude that ATM, despite its myriad functions, is not an absolute requirement for acquiring sufficient levels of immunological diversity to prevent severe viral and opportunistic infections. There is, however, a more clinically pronounced antibody deficiency in ataxia telangiectasia due to disturbed class switch recombination. The functions of ATM are closely intertwined with the processes that generate immunological diversity.The ATM DNA double-stranded break (DSB) response triggers the formation of a network of recruited proteins (including the MRN complex, MDC1, 53BP1) participating in tethering the break ends together.ATM deficiency reduces DSB end tethering, coding end hairpin resolution, and repair, in V(D)J-recombination. This results in a lower success rate of V(D)J recombination, with reduced receptor diversity and increased risk of (oncogenic) translocations in ATM-deficient patients compared with healthy controls.ATM participates in a positive feedback loop in CSR, through phosphorylation of Activation Induced cytidine Deaminase (AID). The end tethering properties of ATM and 53BP1 seem to be more essential for CSR, compared with V(D)J-recombination. Clinically, ATM deficiency primarily causes antibody deficiency.