Chapter 7 - DNA Repair Defects

Abstract

The human cell genome is exposed to DNA damage from various sources. Human cells have mechanisms for self-protection and repair. Genetic instability, predisposition to cancer, and somatic disease occur when these mechanisms are not efficient or are affected by mutations that cause the absence of proteins essential to DNA repair. DNA repair mechanisms can fail and allow mutations during DNA replication, thus becoming a source of diversity. The generation of diversity is important, especially for the immune system. DNA repair defects compromise the balance between generation of diversity and cellular transformation, thus causing disease and immune deficiency. DNA damage also compromises essential cellular processes and leads to mutation and cell death. DNA repair defects include ataxia-telangiectasia, Bloom syndrome, Nijmegen breakage syndrome, and RIDDLE syndrome. DNA repair defects are typically autosomal recessive disorders. They have in common, in their phenotype, the presence of immune deficiency, cellular radiosensitivity, predisposition to cancer, developmental defects, and DNA double-strand break (DSB) repair defects. DSBs occur when both DNA strands are damaged in close proximity; if they are not repaired, the strands physically become disconnected. DSB repair defects are associated with immune deficiency because they compromise V(D)J recombination, lymphocyte maturation, generation of T and B cell receptors, and class switching.