DNA Damage Response: Making it safe to play with knives

(A) Rapid association of Ku to DSBs promotes NHEJ by recruiting DNA-PKcs. Sequential phosphorylation events on multiple DNA-PKcs amino acid clusters favors the initial processing of DNA ends by ARTEMIS, followed by DNA-PKcs-dependent protection of DNA ends required for DNA ligation. (B) Alternatively to NHEJ, MRN, which is initially recruited to DSBs by PARP in competition with Ku, mediates the initial stages of DSB resection together with CtIP and BRCA1 to promote homologous recombination in S and G2. 53BP1 has an inhibitory role on DSB resection and is negatively regulated by BRCA1 by unknown mechanisms. The MRN/CtIP/BRCA1 complex can also promote DSB resection following deprotection of DNA ends when NHEJ fails. Extensive DSB resection and formation of RPA-coated 3′-ssDNA ends is induced by EXO1 and BLM. ATM plays a central role in the regulation of DSB resection as described in the main text. Displacement of RPA from the 3′-ssDNA ends and assembly of RAD51 filaments mediated by BRCA2 leads to strand invasion into homologous DNA sequences. Recruitment of RAD51 to ssDNA ends is regulated by the ATR pathway, which is activated following DSB resection. D-loop structures formed after strand invasion can be cleaved by MUS81/EME1 or displaced by RTEL1 during SDSA to generate crossover or non-crossover events, respectively. Non-crossovers are generated also by dissolution of Holliday junctions (HJs) by the BLM/TOPOIII complex, whereas HJ resolution by the nucleases GEN1 and SLX1/SLX4, which associates with MUS81/EME1, can generate both crossover and non-crossover events. (C) Limited DSB resection carried out by CtIP and MRN in G1 results in alternative NHEJ. (D) Following DSB resection, 3′-ssDNA ends with homologous sequences can be directly annealed by RAD52. Post-translational modifications are indicated as in .

Publication

The DNA Damage Response: Making it safe to play with knives. () Alberto Ciccia, et al. Mol Cell. ;40(2):179-204. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions