MutS preferentially recognizes cisplatin- over oxaliplatin-modified DNA.
Loss of mismatch repair leads to tumor resistance by desensitizing cells to specific DNA-damaging agents, including the anticancer drug cisplatin. Cisplatin analogs with a diamminocyclohexane (DACH) carrier ligand, such as oxaliplatin and Pt(DACH)Cl(2), do not elicit resistance in mismatch repair-deficient cells and therefore present promising therapeutic agents. This study compared the interactions of the purified Escherichia coli mismatch repair protein MutS with DNA modified to contain cisplatin and DACH adducts. MutS recognized the cisplatin-modified DNA with 2-fold higher affinity in comparison to the DACH-modified DNA. ADP stimulated the binding of MutS to cisplatin-modified DNA, whereas it had no effect on the MutS interaction with DNA modified by DACH or EN adducts. In parallel cytotoxicity experiments, methylation-deficient E. coli dam mutants were 2-fold more sensitive to cisplatin than DACH compounds. A panel of recombination-deficient mutants showed striking sensitivity to both compounds, indicating that both types of adducts are strong replication blocks. The differential affinity of MutS for DNA modified with the different platinum analogs could provide the molecular basis for the distinctive cellular responses to cisplatin and oxaliplatin.
Zdraveski
Zoran Z
ZZ
Department of Chemistry and Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Mello
Jill A
JA
Farinelli
Christine K
CK
Essigmann
John M
JM
Marinus
Martin G
MG
D000251:Adenosine Triphosphatases; D000970:Antineoplastic Agents / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D020137:Base Pair Mismatch; D002470:Cell Survival; D002945:Cisplatin / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D004926:Escherichia coli / Q000235:genetics / Q000502:physiology; D029968:Escherichia coli Proteins; D015394:Molecular Structure; D051719:MutS DNA Mismatch-Binding Protein; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000378:metabolism*; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D009944:Organoplatinum Compounds; C057270:cisplatin-DNA adduct; C426283:pt(diaminocyclohexane)Cl2; D000077150:Oxaliplatin; D000251:Adenosine Triphosphatases; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli; D002945:Cisplatin