title: Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems.
abstract: Nucleotide excision repair and the long-patch mismatch repair systems correct abnormal DNA structures arising from DNA damage and replication errors, respectively. DNA synthesis past a damaged base (translesion replication) often causes misincorporation at the lesion site. In addition, mismatches are hot spots for DNA damage because of increased susceptibility of unpaired bases to chemical modification. We call such a DNA lesion, that is, a base damage superimposed on a mismatch, a compound lesion. To learn about the processing of compound lesions by human cells, synthetic compound lesions containing UV photoproducts or cisplatin 1,2-d(GpG) intrastrand cross-link and mismatch were tested for binding to the human mismatch recognition complex hMutS alpha and for excision by the human excision nuclease. No functional overlap between excision repair and mismatch repair was observed. The presence of a thymine dimer or a cisplatin diadduct in the context of a G-T mismatch reduced the affinity of hMutS alpha for the mismatch. In contrast, the damaged bases in these compound lesions were excised three- to fourfold faster than simple lesions by the human excision nuclease, regardless of the presence of hMutS alpha in the reaction. These results provide a new perspective on how excision repair, a cellular defense system for maintaining genomic integrity, can fix mutations under certain circumstances.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill 27599-7260, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mu
authors.forename: M
authors.initials: M
authors.lastname: Tursun
authors.forename: D R
authors.initials: DR
authors.lastname: Duckett
authors.forename: J T
authors.initials: JT
authors.lastname: Drummond
authors.forename: P
authors.initials: P
authors.lastname: Modrich
authors.forename: A
authors.initials: A
authors.lastname: Sancar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D002457:Cell Extracts; D002945:Cisplatin; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D018736:DNA Adducts; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D005656:Fungal Proteins / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009692:Nucleic Acid Heteroduplexes; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011740:Pyrimidine Dimers; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002457:Cell Extracts; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D005656:Fungal Proteins; C088859:MLH1 protein, S cerevisiae; D009692:Nucleic Acid Heteroduplexes; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011740:Pyrimidine Dimers; D029701:Saccharomyces cerevisiae Proteins; C057270:cisplatin-DNA adduct; C094059:cisplatin-deoxy(guanosine monophosphate guanosine) adduct; D004247:DNA; D004706:Endodeoxyribonucleases; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes; D002945:Cisplatin