Investigation of the origins of mutations induced by ultraviolet radiation

Marian Frances Laughery

doi:10.7273/000007406

Ultraviolet (UV) radiation from sunlight is the primary etiological agent responsible for mutations observed in cutaneous skin cancers such as malignant melanoma. Analysis of sequenced melanoma tumors has revealed that they often contain abundant C>T and CC>TT mutations occurring in dipyrimidine contexts. These are collectively classified as UV signature mutations due to their correlation with sites of UV damage formation. It is widely accepted that signature mutations are derived from the mutagenic bypass of cyclobutane pyrimidine dimers (CPDs), which are the most abundant form of DNA damage. Despite this, the mechanism by which they are formed in cellular environments remains unclear. Moreover, UV produces other types of DNA damage, including pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), that form in the same context as CPDs, and the extent to which these contribute to the UV-induced mutation signature is unclear. Investigations of the mutations found in melanoma driver genes indicate that a wide variety of mutations apart from those within the UV signature are involved in oncogenesis, however it remains unclear whether these are similarly derived from UV exposure. The UV radiation component of solar emissions penetrating the earth’s atmosphere is limited to lesser energetic UVA and more energetic UVB subtypes. While it is known that UVA and UVB have widely different effects on DNA, the spectrum of mutations produced by each is less clear, largely due to the limited number of mutations and/or high levels of background mutations present in previous studies. Here, we present our investigations into the origins of diverse UV-induced mutations in the model organism Saccharomyces cerevisiae. We find that UVA and UVB radiation produce highly distinct patterns of mutations reflecting the different types of damage inflicted by each. Specifically, UVA is poorly mutagenic and primarily causes oxidation of guanine bases whereas UVB is highly mutagenic and results in diverse mutations derived from DNA helix-distorting lesions. We further clarify which lesions are responsible for the UVB-induced mutation spectrum and find significant contributions from 6-4PPs and atypical photoproducts in addition to CPDs. Notably, these less common damage types yield mutation classes associated with oncogenic mutations in melanoma, supporting the possible derivation of the latter from sunlight. Finally, we investigate the mechanism of C>T signature mutation formation by developing a method for mapping cytosine deamination of CPDs across the yeast genome and find that this process is significantly influenced by sequence and chromatin contexts in yeast cells. Collectively, our work sheds light on the mutagenic potential of the diverse lesions induced by UV light and clarifies their contributions to observed UV-induced mutation spectra.

Investigation of the origins of mutations induced by ultraviolet radiation

Files and links (1)

Abstract

Metrics

Details