Excision of translesion synthesis errors orchestrates responses to helix-distorting DNA lesions.
J Cell Biol
; 209(1): 33-46, 2015 Apr 13.
Article
in En
| MEDLINE
| ID: mdl-25869665
ABSTRACT
In addition to correcting mispaired nucleotides, DNA mismatch repair (MMR) proteins have been implicated in mutagenic, cell cycle, and apoptotic responses to agents that induce structurally aberrant nucleotide lesions. Here, we investigated the mechanistic basis for these responses by exposing cell lines with single or combined genetic defects in nucleotide excision repair (NER), postreplicative translesion synthesis (TLS), and MMR to low-dose ultraviolet light during S phase. Our data reveal that the MMR heterodimer Msh2/Msh6 mediates the excision of incorrect nucleotides that are incorporated by TLS opposite helix-distorting, noninstructive DNA photolesions. The resulting single-stranded DNA patches induce canonical Rpa-Atr-Chk1-mediated checkpoints and, in the next cell cycle, collapse to double-stranded DNA breaks that trigger apoptosis. In conclusion, a novel MMR-related DNA excision repair pathway controls TLS a posteriori, while initiating cellular responses to environmentally relevant densities of genotoxic lesions. These results may provide a rationale for the colorectal cancer tropism in Lynch syndrome, which is caused by inherited MMR gene defects.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Damage
/
DNA Mismatch Repair
Limits:
Animals
/
Humans
Language:
En
Journal:
J Cell Biol
Year:
2015
Document type:
Article
Affiliation country:
Netherlands