Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System

Abstract

Chromosomal translocations involving antigen receptor loci are common in lymphoid malignancies. Translocations require DNA double-strand breaks (DSBs) at two chromosomal sites, their physical juxtaposition, and their fusion by end joining. Ability of lymphocytes to generate diverse repertoires of antigen receptors and effector antibodies derives from programmed genomic alterations that produce DSBs. We discuss these lymphocyte-specific processes, with a focus on mechanisms that provide requisite DSB target specificity and mechanisms that suppress DSB translocation. We also discuss recent work that provides new insights into DSB repair pathways and influences of three-dimensional genome organization on physiological processes and cancer genomes.

Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

“…51,52 It is also an essential process in the development of the immune response with the purpose of generating enormous antibody diversity of Ig and T-cell receptor genes, thus enabling defense against a wide variety of specific pathogens. 4 Consequently, deficiencies in NHEJ proteins lead to RS-SCID or RS-CID because DSBs are left unrepaired, misrepaired, or repaired with a substantial delay. DSBs are the most significant DNA lesions; unrepaired DSBs can cause cell death, and misrepaired DSBs cause genomic instability and lead to mutations.…”

“…3 Approximately 30% of SCID patients have defects in V(D)J recombination (antigen receptor recombination), an essential process for the normal development of T and B lymphocytes. 4 This process randomly combines variable (V), diverse (D), and joining (J) gene segments in lymphocytes. 5 V(D)J defects lead to T-and Bcell lymphocytopenia and a classic T-B-natural killer þ SCID phenotype.…”

Histone Arginine Methylation by PRMT7 Controls Germinal Center Formation via Regulating Bcl6 Transcription

“…During B cell development, events such as V(D)J recombination, CSR, and SHM lead to chromatin remodeling and DNA damage that make the B cells susceptible to transformation. Defects in the response to DNA damage and genomic instability have been shown to result in immunodeficiency disorders (54). Thus, misregulation of the genes involved in the DNA damage response may be an important reason why resting B cells are impaired in the absence of PRMT7.…”

Reprint of “The clinical impact of deficiency in DNA non-homologous end-joining”

“…In germ line cells, the components of the immunoglobulin and T cell receptor genes are sequentially arranged as distinct arrays of variable (V), diversity (D) or joining (J) segments [36]. During immune development, the gene segments undergo rearrangement via the process of V(D)J recombination to produce distinct re-arrangements of V, D and J sub-fragments.…”

“…During immune development, the gene segments undergo rearrangement via the process of V(D)J recombination to produce distinct re-arrangements of V, D and J sub-fragments. The process of V(D)J recombination has, like NHEJ, been described in several excellent reviews and only an outline will be given here [36][37][38]. In germ line cells, each V, D or J segment has a coding region, C, and a flanking recombination signal sequence (RSS).…”