Atypical UV Photoproducts Induce Non-canonical Mutation Classes Associated with Driver Mutations in Melanoma
Marian F. Laughery,
Alexander J. Brown,
Kaitlynne A. Bohm,
Smitha Sivapragasam,
Haley S. Morris,
Mila Tchmola,
Angelica D. Washington,
Debra Mitchell,
Stephen Mather,
Ewa P. Malc,
Piotr A. Mieczkowski,
Steven A. Roberts,
John J. Wyrick
Affiliations
Marian F. Laughery
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Alexander J. Brown
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Kaitlynne A. Bohm
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Smitha Sivapragasam
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Haley S. Morris
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Mila Tchmola
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Angelica D. Washington
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Debra Mitchell
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Stephen Mather
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA
Ewa P. Malc
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Piotr A. Mieczkowski
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Steven A. Roberts
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA; Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA; Corresponding author
John J. Wyrick
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA; Center for Reproductive Biology, Washington State University, Pullman, WA 99164, USA; Corresponding author
Summary: Somatic mutations in skin cancers and other ultraviolet (UV)-exposed cells are typified by C>T and CC>TT substitutions at dipyrimidine sequences; however, many oncogenic “driver” mutations in melanoma do not fit this UV signature. Here, we use genome sequencing to characterize mutations in yeast repeatedly irradiated with UV light. Analysis of ~50,000 UV-induced mutations reveals abundant non-canonical mutations, including T>C, T>A, and AC>TT substitutions. These mutations display transcriptional asymmetry that is modulated by nucleotide excision repair (NER), indicating that they are caused by UV photoproducts. Using a sequencing method called UV DNA endonuclease sequencing (UVDE-seq), we confirm the existence of an atypical thymine-adenine photoproduct likely responsible for UV-induced T>A substitutions. Similar non-canonical mutations are present in skin cancers, which also display transcriptional asymmetry and dependence on NER. These include multiple driver mutations, most prominently the recurrent BRAF V600E and V600K substitutions, suggesting that mutations arising from rare, atypical UV photoproducts may play a role in melanomagenesis.
