UV light induces cyclobutane pyrimidine dimers (CPDs) and other mutagenic lesions in cellular DNA. Cytosine-containing CPDs can subsequently undergo rapid deamination to uracil, a process that has been linked to UV mutagenesis. However, the impact of genomic context and chromatin architecture on CPD deamination rates in cells remains poorly understood. Here, we develop a method known as dCPD-seq to map deaminated CPDs (dCPDs) across the genome of repair-deficient yeast cells at single-nucleotide resolution. Our dCPD-seq data reveal that sequence context significantly modulates CPD deamination rates in UV-irradiated yeast cells, with CPDs in TCG contexts showing particularly rapid deamination rates. Our analysis indicates that rapid CPD deamination can explain why UV-induced mutations are specifically enriched at TCG sequences, both in UV-irradiated yeast cells and in human skin cancers. CPD deamination is suppressed near the transcription start and end sites of yeast genes, which may in part by mediated by DNA-bound transcription factors. Finally, we show that the wrapping of DNA in nucleosomes modulates CPD deamination in yeast cells. Our data indicate that CPD deamination is elevated at minor-in rotational positions where the DNA minor groove faces the histone octamer, likely owing to increased solvent accessibility of the C4 position of the cytosine base. Moreover, we also observe strand-specific enrichment of CPD deamination at rotational positions where the DNA backbone faces out toward the solvent. Taken together, these findings reveal how DNA sequence context and chromatin architecture modulates CPD deamination rates across a eukaryotic genome.

• PMID: 41365654
• DOI full text
• PubMed
• PubTator

Reference Type

Journal Article

Authors

Laughery MF, Stark B, Morledge-Hampton B, Roberts SA, Wyrick JJ

Primary Lit For

Additional Lit For

Review For