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Review
. 2010 Oct 22;40(2):179-204.
doi: 10.1016/j.molcel.2010.09.019.

The DNA damage response: making it safe to play with knives

Alberto Ciccia  1 , Stephen J Elledge
Affiliations
Review

The DNA damage response: making it safe to play with knives

Alberto Ciccia et al. Mol Cell. .

Abstract

Damage to our genetic material is an ongoing threat to both our ability to faithfully transmit genetic information to our offspring as well as our own survival. To respond to these threats, eukaryotes have evolved the DNA damage response (DDR). The DDR is a complex signal transduction pathway that has the ability to sense DNA damage and transduce this information to the cell to influence cellular responses to DNA damage. Cells possess an arsenal of enzymatic tools capable of remodeling and repairing DNA; however, their activities must be tightly regulated in a temporal, spatial, and DNA lesion-appropriate fashion to optimize repair and prevent unnecessary and potentially deleterious alterations in the structure of DNA during normal cellular processes. This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.

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Figures

Figure 1
Figure 1. Schematic model for ATM and ATR activation in response to DNA damage
(A) Formation of DSBs following IR treatment activates PARP1, which mediates the initial recruitment of the MRN/ATM complex at DSBs. Activation of the ATM kinase activity by MRN and TIP60 leads to the phosphorylation of CHK2 and p53, in addition to a wide number of other DDR factors, and the induction of the γH2AX-dependent signaling cascade, which results in the recruitment of MDC1, RNF8, RNF168, BRCA1 and 53BP1 to DSBs, as described in greater details in the main text. (B) DNA lesions induced by UV light or replication stress (denoted by red rectangular shapes) lead to replication fork stalling and accumulation of RPA-coated ssDNA regions, which recruit the ATR/ATRIP and the RAD17/RFC2-5 complexes. Loading of the 9-1-1 complex by RAD17/RFC2-5 and stimulation of the ATR kinase activity by the 9-1-1 associated protein TOPBP1 result in the activation of the ATR signaling cascade and CHK1 phosphorylation. Post-translational modifications of the DDR factors here depicted are represented by different colored shapes, as indicated by the legend at the bottom of the figure.
Figure 2
Figure 2. Alternative DNA repair pathways involved in the repair of double-strand breaks
(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 Figure 1.
Figure 3
Figure 3. Repair of DNA lesions encountered during DNA replication
(A) Post-replication repair of ssDNA gaps. Leading strand synthesis arrested at DNA lesions (red rectangular shapes) can be reprimed downstream of lesions, leaving ssDNA gaps behind the replication fork. Repair of ssDNA gaps is mediated by RAD6 and RAD18, which are recruited by RPA to ssDNA gaps, where they monoubiquitinate PCNA. Monoubiquitinated PCNA associates with translesion polymerases, which promote lesion bypass. Alternatively, polyubiquitination of PCNA by SHPRH, HLTF and UBC13 induces template switching and strand invasion into homologous sequences of the sister chromatid. Template switching could possibly involve proteins interacting with polyubiquitinated PCNA. Resolution of Holliday junctions formed after strand invasion can then result in sister chromatid exchanges (SCEs), whereas HJ dissolution and SDSA do not generate SCEs. (B) Repair of interstrand crosslinks. Converging replication forks blocked by interstrand crosslinks (red rectangle) activate the FA pathway. The FA core complex associated to blocked replication forks through the FANCM complex promotes the monoubiquitination of the FANCD2/FANCI (ID) complex. Phosphorylation of FANCI by ATR regulates the ubiquitination of the ID complex and its subsequent relocalization to blocked replication forks. Monoubiquitinated ID complex promotes fork cleavage, probably through the interaction with FAN1 and possibly other nucleases, translesion synthesis and crosslink excision. DSB resection, which could be dependent on FAN1, in addition to CtIP/MRN, BLM and EXO1, leads to strand invasion and homologous recombination with or without formation of SCEs as described in (A). Post-translational modifications are indicated as in Figure 1.
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