DNA polymerase η mutational signatures are found in a variety of different types of cancer

Cell Cycle. 2018;17(3):348-355. doi: 10.1080/15384101.2017.1404208. Epub 2018 Feb 15.


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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA-Directed DNA Polymerase / genetics*
  • Exome / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mutation / genetics*
  • Neoplasms / enzymology*
  • Neoplasms / genetics*
  • Skin / pathology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology


  • DNA-Directed DNA Polymerase
  • Rad30 protein