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Cells are continuously faced with endogenous stress (for example, during replication) and exogenous stress (for example, during exposure to ultraviolet radiation) that can ultimately lead to DNA damage. To preserve genomic integrity, cells have an arsenal of repair proteins that engage the appropriate repair pathway or, if damage is irreparable, induce cell cycle arrest and/or apoptosis. This article series explores the pathways that detect and repair different types of DNA damage, highlighting new regulation mechanisms of the DNA damage response and the implications of disrupted DNA repair for disease.
DNA polymerase theta (Polθ)-mediated end joining is a recently characterized DNA repair pathway that functions in various cellular contexts to repair DNA double-strand breaks that are not repaired by other pathways. Polθ-mediated end joining both helps maintain the genome and causes genome instability, and is an emerging therapeutic target in cancer.
Deficiency in the protein kinase ATM — a master regulator of double-strand DNA breaks and stress responses — causes ataxia telangiectasia (A-T). Recent studies link A-T with other neurodegenerative disorders, and implicate reactive oxygen species, mitochondrial dysfunction, defects in proteostasis and metabolism, and increased poly(ADP-ribosyl)ation in the aetiology of A-T.
Non-homologous DNA end joining (NHEJ) is the main repair pathway of DNA double-strand breaks. Recent studies show that synapsis — the crucial pairing of DNA ends — is performed by several mechanisms, and this insight can now be integrated with updates on the DNA end processing and ligation steps of NHEJ, and with NHEJ-related human diseases.
BRCA1 and its partner BARD1 support repair of double-strand breaks by homologous recombination and protect replication forks from damage. Recent studies have improved our understanding of the molecular mechanisms of these tumour-suppressive functions of BRCA1–BARD1 and how they are subverted in therapy-resistant cancers.
Transcription-blocking DNA lesions (TBLs) cause transcription stress and are repaired by transcription-coupled nucleotide excision repair (TC-NER). TBL detection by the stalling of RNA polymerase II is highly efficient but may interfere with repair, and overall with transcription and replication. Consequently, TC-NER deregulation causes hereditary disorders with complex genotype–phenotype correlations.
The choice between the major DNA double-strand break repair pathways is important for maintaining genomic stability. In mammals, selecting one pathway over another involves a complex series of binary ‘decisions’. Emerging evidence suggests that the ‘decision tree’ governing repair-pathway choice at stalled replication forks differs from that of replication-independent double-strand breaks.
Recent insights into the roles of poly(ADP-ribose) polymerase 1 (PARP1) in mediating various DNA repair pathways, stabilizing DNA replication and modulating chromatin structure are being exploited clinically for the treatment of DNA repair-deficient cancers.
Covalent DNA–protein crosslinks (DPCs) are induced by various compounds, which include widely used anticancer drugs, and are highly cytotoxic. Recent studies have revealed the mechanisms and the regulation of DPC repair pathways and suggest that components of these pathways can serve as targets for anticancer therapies.
In mammalian cells, DNA double-strand breaks (DSBs) are repaired predominantly by the non-homologous end joining (NHEJ) pathway, which includes subpathways that can repair different DNA-end configurations. Furthermore, the repair of some DNA-end configurations can be shunted to the auxiliary pathways of alternative end joining (a-EJ) or single-strand annealing (SSA).
Structure-specific endonucleases (SSEs) function in concert with other DNA-remodelling enzymes and cell cycle control machineries in processes such as DNA adduct repair, Holliday junction processing and the response to replication stress. As SSEs have specificity for DNA structures rather than sequence, tight regulation of their activity is important to ensure genome stability.