The mismatch-repair protein hMSH2 binds selectively to DNA adducts of the anticancer drug cisplatin.
BACKGROUND
The antitumor drug cis-diamminedichloroplatinum(II) (cis-DDP or cisplatin) exerts its cytotoxic effects through the formation of covalent DNA adducts. A family of proteins possessing a common HMG box motif that binds specifically to cisplatin DNA adducts has been previously suggested to be important in the clinical efficacy of the drug.


RESULTS
We have shown that the human mismatch-repair protein, hMSH2, also binds specifically to DNA containing cisplatin adducts and displays selectivity for the DNA adducts of therapeutically active platinum complexes. Moreover, hMSH2 is overexpressed in testicular and ovarian tissue; tumors in these tissues are most effectively treated by cisplatin.


CONCLUSIONS
Our results suggest a role for hMSH2 in mediating cisplatin toxicity. Supporting this view, previous studies in Escherichia coli dam- strains demonstrate that mutations in mismatch-repair proteins confer resistance to cisplatin toxicity. Mismatch-repair deficiency is also correlated with tolerance to O6-methylguanine, a cytotoxic DNA lesion formed by methylating agents. A current model ascribes O6-methylguanine toxicity to unsuccessful attempts at repair of this lesion by mismatch-repair proteins, resulting in a futile cycle of incision and synthesis, leading ultimately to lethal DNA-strand breaks. We propose that mismatch repair may contribute to cisplatin toxicity by a similar mechanism. Alternatively, hMSH2 may shield cisplatin adducts from repair, allowing adducts to persist, thus enhancing lethality.
Mello
J A
JA
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. jessig@mit.edu
Acharya
S
S
Fishel
R
R
Essigmann
J M
JM
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002945:Cisplatin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D003432:Cross-Linking Reagents; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005656:Fungal Proteins; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D051718:MutS Homolog 2 Protein; D010053:Ovary / Q000378:metabolism; D010984:Platinum; D011485:Protein Binding; D013737:Testis / Q000378:metabolism; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C057270:cisplatin-DNA adduct; D010984:Platinum; D051718:MutS Homolog 2 Protein; D002945:Cisplatin