Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations.
Nucleic Acids Res
; 49(9): 5084-5094, 2021 05 21.
Article
en En
| MEDLINE
| ID: mdl-33877329
ABSTRACT
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 TG 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 TG mismatch increased CEBPß binding affinity by a factor of >60 relative to the normal CG 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 UG DNA mismatch that is normally repaired via uracil DNA glycosylase, is also inhibited by CEBPß binding. Passage of a replication fork over either a TG or UG 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Disparidad de Par Base
/
Proteínas Potenciadoras de Unión a CCAAT
Límite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos