Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations.
- Additional Document Info
- View All
DNA cytosine methylation in mammals modulates gene expression and chromatin accessibility. It also impacts mutation rates, via spontaneous oxidative deamination of 5-methylcytosine (5mC) to thymine. In most cases the resulting T:G mismatches are repaired, following T excision by one of the thymine DNA glycosylases, TDG or MBD4. We found that C-to-T mutations are enriched in the binding sites of CCAAT/enhancer binding proteins (CEBP). Within a CEBP site, the presence of a T:G mismatch increased CEBPβ binding affinity by a factor of >60 relative to the normal C:G base pair. This enhanced binding to a mismatch inhibits its repair by both TDG and MBD4 in vitro. Furthermore, repair of the deamination product of unmethylated cytosine, which yields a U:G DNA mismatch that is normally repaired via uracil DNA glycosylase, is also inhibited by CEBPβ binding. Passage of a replication fork over either a T:G or U:G mismatch, before repair can occur, results in a C-to-T mutation in one of the daughter duplexes. Our study thus provides a plausible mechanism for accumulation of C-to-T human somatic mutations.
author list (cited authors)
Yang, J., Horton, J. R., Akdemir, K. C., Li, J., Huang, Y., Kumar, J., ... Cheng, X.
complete list of authors
Yang, Jie||Horton, John R||Akdemir, Kadir C||Li, Jia||Huang, Yun||Kumar, Janani||Blumenthal, Robert M||Zhang, Xing||Cheng, Xiaodong