ATM: Translating the DNA Damage Response to Adaptive Immunity

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. 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. 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. uncommon DNA DSB repair pathway using relatively small microhomologies (<25 base pairs) to align ssDNA overhangs of DSB ends having undergone low levels of end resection. Often results in small deletions or translocation. material from the mouth or stomach (e.g., food) entering the respiratory system (lungs). lack of muscle control and coordination, affecting movement, balance, and speech. Often caused by neurodegenerative diseases. process in which a B cell changes isotype, and therefore effector function, of its produced immunoglobulin. frequently diagnosed primary immunodeficiency, also in adults. Heterogeneous disease characterized by antibody deficiency, poor response to vaccination, susceptibility to infections, autoimmunity, and cancer predisposition. a different mutation on each of the two alleles of a gene locus (i.e., on both chromosomes). the multitude of proteins recruited and activated in DNA damage repair. difficulty swallowing (e.g., food). ability of DNA-repair proteins to hold the ends of dsDNA breaks in close proximity, allowing repair and translocation, benefiting genomic stability. insertions and deletions of nucleotides that disrupt the reading frame of all codons being read from the mutation onwards; results in instability and loss of protein. phenomenon of mRNA production at the gene loci of adaptive immunity receptors, without translation occurring afterwards. This process occurs solely to render these loci more open and accessible to the effector proteins of V(D)J-recombination and class switch recombination (i.e., RAG proteins and AID, respectively). most accurate repair pathway for DSB DNA damage. Genetic recombination occurs through strand invasion of the S-phase generated sister chromatid, allowing repair through exchange of information between two homologous DNA molecules. joining of one signal end to the coding end of the other recombination signal sequence, usually through inversion of the DNA in between the RAG-induced breaks. primary immunodeficiency characterized by increased serum IgM and an inability to switch antibody production to IgG, IgA, or IgE. Results in increased risk of, mostly sinopulmonary, bacterial infections. extensive resection of DSB ends, resulting in long 3′ ssDNA overhangs required for (micro-)homology-mediated DSB repair pathways, such as alternative end joining and homologous recombination. through differential nucleotide additions in the coding joints by the enzyme Terminal deoxynucleotidyl Transferase (TdT), as well as differential hairpin end opening by nuclease Artemis, immune cells can introduce extra immunological diversity in the produced antigen receptors during V(D)J-recombination. primary repair pathway for DNA DSB, in which the break ends are ligated without the need for a homologous template. single nucleotide mutation causing a premature stop codon during translation, often resulting in instability and loss of the protein, although sometimes in a shorter, often nonfunctional protein. occur more often or are more severe in patients with immunodeficiency. after cleavage at the recombination signal sequences by the RAG-nucleases in V(D)J-recombination, the RAG proteins stay in complex with the DNA DSB. This depends on the C terminal of RAG2 and promotes end tethering and repair. variation in antigen receptors in adaptive immunity; includes differential use of the VDJ-gene segment building blocks, as well as differences in junctional editing. rare primary immunodeficiency; symptoms: radiosensitivity, mild immunodeficiency, dysmorphic features, and difficulties learning. involves both cellular (T cell) and humoral (B cell) immunity. Characterized by high morbidity and mortality due to infections. alternative, uncommon repair pathway of DNA DSB, following more extensive end resection. Uses homology (>20 nucleotides) between the two excised ssDNA overhangs on both sides of the breaks. Results in loss of any extra overhanging nucleotides, causing larger deletions. diluted small blood vessels visible on body surfaces (e.g., skin or conjunctivas).