DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol η mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase η are a common feature of tumorigenesis. Another peculiarity of pol ηmutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol η in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.

b Department Microbiology and Molecular Genetics University of California Davis CA USA

c Rutgers Cancer Institute of New Jersey Rutgers University New Brunswick NJ USA

e Systems Biology Center Icahn School of Medicine at Mount Sinai New York New York 10029 USA

f Institute of Medical Genetics School of Medicine Cardiff University UK

g Eppley Institute for Research in Cancer and Allied Diseases University of Nebraska Medical Center Omaha NE 68198 USA

h Departments of Microbiology and Pathology University of Nebraska Medical Center Omaha NE USA

i Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha NE USA

j Genetics Cell Biology and Anatomy University of Nebraska Medical Center Omaha NE USA

Life Science Research Center University of Ostrava 71000 Ostrava Czech Republic

National Center for Biotechnology Information National Library of Medicine National Institutes of Health Bethesda MD USA

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DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers

Diverse roles of RAD18 and Y-family DNA polymerases in tumorigenesis