FIGURE 1 | Pathways that respond to double-strand breaks.

a | Homologous recombination (HR) takes place in late S–G2 phase and involves the generation of a single-stranded region of DNA, followed by strand invasion, formation of a Holliday junction, DNA synthesis using the intact strand as a template, branch migration and resolution. Non-homologous end-joining (NHEJ) takes place throughout the cell cycle and involves binding of the KU heterodimer to double-stranded DNA ends, recruitment of DNA-PKcs (officially known as protein kinase, DNA-activated, catalytic polypeptide (PRKDC)), processing of ends (including Artemis-dependent processing) and recruitment of the DNA ligase IV (LIG4)–XRCC4 complex, which brings about ligation. The ataxia telangiectasia mutated (ATM) protein affects NHEJ as it is required for Artemis-dependent end processing. ATM signalling is the main signal-transduction process that responds to a DSB. Ataxia telangiectasia and RAD3-related (ATR) signalling is activated later after irradiation, probably when radiation-induced lesions block replication. Both pathways lead to cell-cycle-checkpoint activation, which allows more time for repair or permanently prevents the proliferation of damaged cells. An important step in ATM- and ATR-dependent signalling is phosphorylation of H2A histone family, member X (H2AFX) and recruitment of the mediator proteins, mediator of DNA damage checkpoint 1 (MDC1), tumour protein 53 binding protein 1 (TP53BP1) and the MRN (MRE11–RAD50–NBS1) complex. Additional proteins, such as structural maintenance of chromosomes 1 (SMC1), are also recruited to the site of damage. Other proteins that are recruited to the foci, such as replication protein A (RPA) and Bloom syndrome (BLM), have not been shown for clarity. ATR signalling is activated by single-stranded regions of DNA that arise, for example, at stalled replication forks. RPA coats single-stranded DNA and recruits ATR and its partner ATRIP (ATR-interacting protein). H2AFX phosphorylation, recruitment of mediator proteins and downstream phosphorylation occur in a process that is similar to the ATM-dependent pathway, although with some distinctions (for example, CHEK1 and CHEK2 (checkpoint 1 and 2) might be differently phosphorylated by ATM versus ATR). HR probably depends on ATR, either to stabilize stalled replication forks and/or to activate the process of HR. DNA crosslinks are repaired through a process that probably generates a DSB as an intermediate. b | DDR syndromes in which pathways that respond to DSBs are affected. AT, ataxia telangiectasia; ATLD, ataxia telangiectasia-like disorder; FA, Fanconi anaemia; FANCD2, Fanconi anaemia complementation group D2; NBS, Nijmegen breakage syndrome; PNK, polynucleotide kinase.

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