title: Excision of translesion synthesis errors orchestrates responses to helix-distorting DNA lesions.
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.
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Anastasia
authors: A
authors: Tsaalbi-Shtylik
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Cristina
authors: C
authors: Ferrás
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Bea
authors: B
authors: Pauw
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Giel
authors: G
authors: Hendriks
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Piya
authors: P
authors: Temviriyanukul
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Leone
authors: L
authors: Carlée
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Fabienne
authors: F
authors: Calléja
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Sandrine
authors: S
authors: van Hees
authors: Faculty of Science, Gakushuin University, Tokyo 171-0031, Japan.
authors: Jun-Ichi
authors: J
authors: Akagi
authors: School of Engineering Science, Osaka University, Osaka 565-0871, Japan.
authors: Shigenori
authors: S
authors: Iwai
authors: Faculty of Science, Gakushuin University, Tokyo 171-0031, Japan.
authors: Fumio
authors: F
authors: Hanaoka
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.
authors: Jacob G
authors: JG
authors: Jansen
authors: Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands n.de_wind@lumc.nl.
authors: Niels
authors: N
authors: de Wind
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004249:DNA Damage; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000502:physiology; D053595:Embryonic Stem Cells / Q000502:physiology; D004843:Epistasis, Genetic; D006801:Humans; D057507:Mice, 129 Strain; D051718:MutS Homolog 2 Protein / Q000502:physiology; D016296:Mutagenesis
chemical_list: D004268:DNA-Binding Proteins; C102997:Msh6 protein, mouse; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein