TY - JOUR T1 - Identification of Transdominant-Negative Genetic Suppressor Elements Derived from hMSH2 That Mediate Resistance to 6-Thioguanine JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1198 LP - 1206 DO - 10.1124/mol.62.5.1198 VL - 62 IS - 5 AU - Maida M. de las Alas AU - Gerrit Los AU - Xinjian Lin AU - Buran Kurdi-Haidar AU - Gerald Manorek AU - Stephen B. Howell Y1 - 2002/11/01 UR - http://molpharm.aspetjournals.org/content/62/5/1198.abstract N2 - Using random screening for genetic suppressor elements, we sought to identify portions of hMSH2 important to the ability of the mismatch repair system to recognize and process DNA adducts that mimic mismatches. All recovered candidate genetic suppressor elements were derived from the region containing amino acids 782 to 844. Expression of a peptide corresponding to this region partially disabled mismatch repair as evidenced by 1.5- to 3.3-fold resistance to 6-thioguanine, cisplatin, andN-methyl-N′-nitrosoguanidine, an increase in the rate of generation of drug resistant variants, and the appearance of microsatellite instability. Even low-level expression of this protein was sufficient to partially impair mismatch repair. The results suggest that this region is important to the ability of the mismatch repair system to mediate drug sensitivity and to maintain genomic stability. ER -