Damage mapping techniques and the light they have shed on canonical and atypical UV photoproducts

Abstract

Ultraviolet (UV) light is a pervasive threat to the DNA of terrestrial organisms. UV light induces helix-distorting DNA lesions, primarily cyclobutane pyrimidine dimers (CPDs) that form between neighboring pyrimidine bases. Unrepaired CPD lesions cause cytosine-to-thymine (C>T) substitutions in dipyrimidine sequences, which is the predominant mutation class in skin cancer genomes. However, many driver mutations in melanoma (e.g., in the BRAF and NRAS oncogenes) do not fit this UV mutation signature. Recent studies have brought to light the intriguing hypothesis that these driver mutations may be induced by infrequent or atypical UV photoproducts, including pyrimidine 6-4 pyrimidone photoproducts (6-4PP) and thymine-adenine (TA) photoproducts. Here, we review innovative methods for mapping both canonical and atypical UV-induced photoproducts across the genome.

Keywords: 6-4 photoproduct; CPD; hotspot; melanoma; mutation; nucleosome; thymine-adenine photoproduct; transcription factor.

FIGURE 1

Schematic of atypical thymine-adenine (TA-PP) and cytosine-adenine photoproduct (CA-PP) formation. Upon UVC exposure, neighboring nitrogenous bases of a 5’ thymine and 3’ adenine will form covalent bonds at C5 and C6 to form an unstable [2 + 2] intermediate structure, that finalizes as the TA-PP (structure adapted from Wang et al., 2001). Similarly, as discussed in Su et al. (2010), methylated cytosines (methyl group shown in red) within a 5’-^mCA-3’ context have the ability to form a CA-PP following UVB exposure, that then may deaminate to form a TA-PP.