Recent advances in the study of immunodeficiency and DNA damage response

• Published in: International Journal of Hematology Vol. 106; no. 3; pp. 357 - 365
• Main Author: Morio, Tomohiro
• Format: Journal Article
• Language: English
• Published: Tokyo Springer Science and Business Media LLC 01.09.2017; Springer Japan; Springer Nature B.V
• Subjects: Activation-induced cytidine deaminase; Antigens; Ataxia; Ataxia telangiectasia; Class switching; Cytidine deaminase; Damage detection; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; DNA Repair - genetics; DNA-dependent protein kinase; Double-strand break repair; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation - adverse effects; Homology; Humans; Hyper-IgM Immunodeficiency Syndrome; Hyper-IgM Immunodeficiency Syndrome - genetics; Immunoglobulin Class Switching; Immunoglobulin Class Switching - genetics; Immunoglobulin M; Job's syndrome; Medicine; Medicine & Public Health; Mismatch repair; MRE11 protein; Non-homologous end joining; Oncology; Progress in Hematology; Protein kinase C; Radiosensitivity; RAG1 protein; Repair; Severe Combined Immunodeficiency; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - therapy; T cell receptors; Toxicity; Transplantation; V(D)J Recombination; V(D)J Recombination - genetics; Class switch recombination; DNA damage response; Immunodeficiency; V(D)J recombination
• ISSN: 0925-5710; 1865-3774; 1865-3774
• DOI: 10.1007/s12185-017-2263-8

DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome. In V(D)J recombination, DSBs are induced by RAG1/2; and generated post-cleavage hairpins are resolved by Artemis/DNA-PKcs/KU70/KU80. DDR is initiated by ataxia-telangiectasia mutated as a master regulator together with MRE11/RAD50/NBS1 complex. Finally, DSBs are repaired by NHEJ. The defect of one of the molecules shows various degree of immunodeficiency and radiosensitivity. Upon CSR inducing signal, DSBs induced by activation-induced cytidine deaminase and endonucleases elicit DDR. Broken ends are repaired either by NHEJ or by mismatch repair system. Patients with radiosensitive SCID require hematopoietic cell transplantation as a curative therapy; but the procedures for eradication of recipient hematopoietic cells are often associated with severe toxicity.