Hypermutation; POLH; mutable motif; DNA lesion bypass; sloppy DNA polymerase; skin cancer; gene expression profiles

DNA polymerase (pol) 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 can compromise genome integrity. We explored whether the mutational signature of pol 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 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 are a common feature of tumorigenesis. Another peculiarity of pol mutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.