Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct.
Bacterial and mammalian mismatch repair systems have been implicated in the cellular response to certain types of DNA damage, and genetic defects in this pathway are known to confer resistance to the cytotoxic effects of DNA-methylating agents. Such observations suggest that in addition to their ability to recognize DNA base-pairing errors, members of the MutS family may also respond to genetic lesions produced by DNA damage. We show that the human mismatch recognition activity MutSalpha recognizes several types of DNA lesion including the 1,2-intrastrand d(GpG) crosslink produced by cis-diamminedichloroplatinum(II), as well as base pairs between O6-methylguanine and thymine or cytosine, or between O4-methylthymine and adenine. However, the protein fails to recognize 1,3-intrastrand adduct produced by trans-diamminedichloroplatinum(II) at a d(GpTpG) sequence. These observations imply direct involvement of the mismatch repair system in the cytotoxic effects of DNA-methylating agents and suggest that recognition of 1,2-intrastrand cis-diamminedichloroplatinum(II) adducts by MutSalpha may be involved in the cytotoxic action of this chemotherapeutic agent.
Duckett
D R
DR
Howard Hughes Medical Institute and Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Drummond
J T
JT
Murchie
A I
AI
Reardon
J T
JT
Sancar
A
A
Lilley
D M
DM
Modrich
P
P
D000251:Adenosine Triphosphatases; D001426:Bacterial Proteins / Q000378:metabolism*; D001482:Base Composition; D001483:Base Sequence; D002945:Cisplatin / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D029968:Escherichia coli Proteins; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D051719:MutS DNA Mismatch-Binding Protein; D011485:Protein Binding; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D015226:Dinucleoside Phosphates; D029968:Escherichia coli Proteins; C094059:cisplatin-deoxy(guanosine monophosphate guanosine) adduct; C021223:O-4-methylthymine; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D000251:Adenosine Triphosphatases; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli; D002945:Cisplatin; D013941:Thymine