Details

Autor(en) / Beteiligte

• Perez, Brian S.
• Wong, Ka Man
• Schwartz, Erin K.
• Herrera, Rafael E.
• King, Devin A.
• García-Nieto, Pablo E.
• Morrison, Ashby J.

Titel

Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma

Ist Teil von

• Mutation research, 2021-07, Vol.823, p.111758-111758, Article 111758

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• •Across the genome, 6-4PP and CPD lesions have broadly similar distributions.•Chromatin at bivalent and Polycomb-repressed enhancers are differentially susceptible to 6-4PPs.•Genes and enhancers more susceptible to 6-4PPs than CPD are associated with cell viability and immune-related pathways.•Both 6-4PP and CPD lesions correlate with C > T mutation rates across the genome. Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.