XPC lymphoblastoid cells defective in the hMutSalpha DNA mismatch repair complex exhibit normal sensitivity to UVC radiation and normal transcription-coupled excision repair of DNA cyclobutane pyrimidine dimers.
Nucleotide excision (NER) is generally considered to comprise two partially distinct subpathways. Global genomic repair (GGR) removes damage from the genome overall and transcription-coupled repair (TCR) selectively excises damage from transcribed DNA. Cells from individuals belonging to xeroderma pigmentosum (XP) complementation group C are defective in GGR but retain a functional TCR pathway. DNA mismatch repair (MMR) corrects replication errors but can also process DNA damage. It has been suggested that the essential hMutSalpha and hMutLalpha MMR protein complexes are also required for effective excision of UV-induced cyclobutane pyrimidine dimers (CPD) by TCR. We have combined an MMR and an XPC defect in a human lymphoblastoid cell line. The MMR-defective XPC cells were defective in the hMutSalpha mismatch recognition complex that comprises hMSH2 and hMSH6. They were not detectably more sensitive to killing by UV than their MMR proficient counterparts and were able to excise CPDs from an actively transcribed DNA strand. We conclude efficient TCR does not depend on a functional hMutSalpha complex.
Kobayashi
Katsutoshi
K
Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
O'Driscoll
Mark
M
Macpherson
Peter
P
Mullenders
Leon
L
Vreeswijk
Maaike
M
Karran
Peter
P
D000477:Alkylating Agents / Q000009:adverse effects; D020137:Base Pair Mismatch; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D004351:Drug Resistance; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000528:radiation effects; D008770:Methylnitrosourea / Q000009:adverse effects; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D011740:Pyrimidine Dimers / Q000378:metabolism*; D011836:Radiation Tolerance; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D000477:Alkylating Agents; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011518:Proto-Oncogene Proteins; D011740:Pyrimidine Dimers; C086984:XPC protein, human; D008770:Methylnitrosourea; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein