Enhanced C/EBP binding to G·T mismatches facilitates fixation of CpG mutations in cancer and adult stem cells

Cell Rep. 2021 Jun 8;35(10):109221. doi: 10.1016/j.celrep.2021.109221.


Somatic mutations in regulatory sites of human stem cells affect cell identity or cause malignant transformation. By mining the human genome for co-occurrence of mutations and transcription factor binding sites, we show that C/EBP binding sites are strongly enriched with [C > T]G mutations in cancer and adult stem cells, which is of special interest because C/EBPs regulate cell fate and differentiation. In vitro protein-DNA binding assay and structural modeling of the CEBPB-DNA complex show that the G·T mismatch in the core CG dinucleotide strongly enhances affinity of the binding site. We conclude that enhanced binding of C/EBPs shields CpG·TpG mismatches from DNA repair, leading to selective accumulation of [C > T]G mutations and consequent deterioration of the binding sites. This mechanism of targeted mutagenesis highlights the effect of a mutational process on certain regulatory sites and reveals the molecular basis of putative regulatory alterations in stem cells.

Keywords: C/EBP; CEBPB; CpG methylation; DNA mismatch; adult stem cells; cancer cells; somatic mutagenesis; somatic mutations; transcription factor binding sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / metabolism*
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Dinucleoside Phosphates / metabolism*
  • Humans
  • Mutation
  • Neoplasms / genetics*


  • CCAAT-Enhancer-Binding Protein-alpha
  • Dinucleoside Phosphates
  • cytidylyl-3'-5'-guanosine