Epigenetic regulation of genomic integrity

Abstract

Inefficient and inaccurate repair of DNA damage is the principal cause of DNA mutations, chromosomal aberrations, and carcinogenesis. Numerous multiple-step DNA repair pathways exist whose deployment depends on the nature of the DNA lesion. Common to all eukaryotic DNA repair pathways is the need to unravel the compacted chromatin structure to facilitate access of the repair machinery to the DNA and restoration of the original chromatin state afterward. Accordingly, our cells utilize a plethora of coordinated mechanisms to locally open up the chromatin structure to reveal the underlying DNA sequence and to orchestrate the efficient and accurate repair of DNA lesions. Here we review changes to the chromatin structure that are intrinsic to the DNA damage response and the available mechanistic insight into how these chromatin changes facilitate distinct stages of the DNA damage repair pathways to maintain genomic stability.

Fig. 1

Role of chromatin in amplification of the DDR at a DSB site. As discussed in the text, in response to a DSB, the chromatin structure locally relaxes, facilitating the activation and recruitment of the ATM kinase. Phosphorylation of H2AX by ATM enables recruitment of many proteins including MDC1. ATM-mediated phosphorylation of MDC1 enables further amplification of the DNA damage response. DNA is shown in blue and histones are beige, and the wiggly DNA in nucleosomes around the DSB depict those that have been acted upon by ATP-dependent nucleosome remodelers, to facilitate access to the DNA

Fig. 2

Role of chromatin in recruitment of mediators of the DDR to DSB sites. The steps shown in this figure follow on from those in Fig. 1. MDC1 promotes the dimethylation of H4 K20 via recruiting MMSET which in turn is recognized by the 53BP1 checkpoint mediator protein. MDC1 also promotes ubiquitinylation of H2A by recruiting the p400 ATP-dependent nucleosome remodeler and the RNF8 E3 ligase. RNF168 acts after RNF8 to generate a polyubiquitin tail on H2A, which in turn serves to recruit the BRCA1-A checkpoint mediator complex to the DSB site. 53BP1 favors NHEJ over homologous recombination, while the BRCA1-C complex containing the phosphorylated CtIP endonuclease overcomes the repressive effect of 53BP1 on homologous recombination

Fig. 3

Chromatin dynamics during repair of heterochromatinized DSBs. DSBs within heterochromatin are efficiently and rapidly recognized by the DNA damage checkpoint machinery leading to phosphorylation of H2AX (shown by the green p). The chromatin within the heterochromatin compartment next becomes highly mobile and dynamic, resulting in the movement of the DSB to the periphery of the heterochromatin compartment. Once at the periphery, homologous recombination can occur due to the recruitment of proteins such as Rad51, which are blocked from association with the DSB within the heterochromatin compartment by the Smc5/6 proteins

Fig. 4

Reestablishment of chromatin after DSB repair. DNA resection in yeast is accompanied by loss of the histones from the DNA being processed. Phosphorylated H2AX either gets dephosphorylated or those histones get removed from the chromatin and replaced with unphosphorylated histones (termed histone exchange). Following DNA repair, histone chaperones such as CAF-1 bring in new histone carrying the H3 K56Ac mark onto the repaired DNA, serving as a signal to the DNA damage checkpoint that repair is now complete

Fig. 5

Role of chromatin in NER. DNA distortion that is caused by UV-induced DNA damage (a CPD is shown for example) is recognized by the XPC–HR23B–centrin2 and DDB1–DDB2 complexes. DDB1–DDB2 recruits histone acetyl transferases (shown in red) to the site of the DNA lesion, inducing histone acetylation to further loosen the chromatin structure. For lesions within heterochromatin, H3 K9 is demethylated by KDMB4 to facilitate NER. Histone loss presumably accompanies the excision and removal of the damaged DNA strand, and this is followed by CAF-1 mediated chromatin assembly over the repaired DNA region