Organization of DNA damage, excision repair, and mutagenesis in chromatin: A genomic perspective

Abstract

Genomic DNA is constantly assaulted by both endogenous and exogenous damaging agents. The resulting DNA damage, if left unrepaired, can interfere with DNA replication and be converted into mutations. Genomic DNA is packaged into a highly compact yet dynamic chromatin structure, in order to fit into the limited space available in the nucleus of eukaryotic cells. This hierarchical chromatin organization serves as both the target of DNA damaging agents and the context for DNA repair enzymes. Biochemical studies have suggested that both the formation and repair of DNA damage are significantly modulated by chromatin. Our understanding of the impact of chromatin on damage and repair has been significantly enhanced by recent studies. We focus on the nucleosome, the primary building block of chromatin, and discuss how the intrinsic structural properties of nucleosomes, and their associated epigenetic modifications, affect damage formation and DNA repair, as well as subsequent mutagenesis in cancer.

Keywords: Base excision repair; Mutagenesis; Nucleosome; Nucleotide excision repair; Skin cancer; UV damage.

Figure 1:. Nucleosome translational and rotational settings regulate UV damage formation, DNA repair, and cancer mutagenesis.

NER activity is inhibited at the nucleosome dyad center, which is associated with increased mutation density in melanoma. At inward-facing rotational settings (‘in’), where the DNA minor groove faces toward histones, both UV damage formation and deamination of methylated cytosine in CPDs are reduced, which is associated with decreased mutations at ‘in’ rotational positions in melanoma. BER activity is decreased at ‘in’ rotational settings, which may contribute to the high mutation frequency at ‘in’ positions in esophageal and gastric cancer. However, further studies are needed to establish the direct correlation between BER and cancer mutation variations in the nucleosome. In contrast to the ‘in’ positions, UV damage formation, deamination of methylated cytosine in CPDs, and BER activity are elevated at ‘out’ rotational settings.

Figure 2:. ETS binding promotes UV damage formation and melanoma mutations.

DNA binding by ETS transcription factors significantly induces UV damage formation. The UV damage hotspots at ETS binding sites are associated with highly recurrent non-coding mutations in melanoma, which may alter transcription of ETS target genes.

Figure 3:. Open and closed chromatin states significantly affect excision repair and cancer mutation distribution.

DNA damage (e.g., UV, cisplatin, or benzo[a]pyrene adducts) in open chromatin regions is repaired more efficiently, while damage in closed chromatin such as heterochromatin is repaired less efficiently. Consequently, high mutation densities in cancer are frequently found in closed chromatin, while low mutation densities are associated with an open chromatin state.