DNA Strand Break Repair and Human Genetic Disease

Abstract

Deoxyribonucleic acid (DNA) is constantly exposed to exogenous and endogenous DNA damaging agents. Among the different types of DNA damage that arise in the cells, single‐strand breaks (SSBs) and double‐strand breaks (DSBs) are a serious threat to genetic integrity and cell survival. To minimise the impact of these lesions, cells have evolved various DNA repair mechanisms depending on the kind of DNA damage. The importance of DNA strand break repair is highlighted by the observation that many proteins involved in the repair pathways are mutated in a wide variety of cancers and in different types of hereditary diseases. These disorders display a variety of features. Notably, syndromes related with defects in the repair of single‐strand breaks exhibit a pathology that is restricted to cerebellar ataxia and neurodegeneration, whereas DSB repair syndromes exhibit a more diverse pathology and can include developmental abnormalities, microcephaly and cancer predisposition. Key Concepts: The DNA damage response (DDR) is a signal transduction pathway that starts with the sensing of the damage and coordinates cell cycle, repair and apoptosis. DDR plays an important role in development and preservation of genome stability and, consequently, is crucial for cancer prevention and normal ageing. Many proteins involved in DNA repair pathways are mutated in a wide variety of cancers and in different types of hereditary diseases. Homologous recombination is a DNA repair pathway linked to replication and devoted to the repair of DNA breaks using an intact DNA template to copy information. Nonhomologous end‐joining (NHEJ) is a double‐strand break repair pathway that ligates the two ends without using any DNA template. DSB repair syndromes exhibit a diverse pathology and can include developmental abnormalities, microcephaly and cancer predisposition. Syndromes with impaired NHEJ also show dramatic immunological defects highlighting the role of NHEJ during development of the immunological system. Syndromes related with defects in the repair of single‐strand breaks exhibit a pathology that is restricted to cerebellar ataxia and neurodegeneration.