Identification of transdominant-negative genetic suppressor elements derived from hMSH2 that mediate resistance to 6-thioguanine.
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, and N-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.
de las Alas
Maida M
MM
Cancer Center, University of California, San Diego, La Jolla, California, USA. mdelasalas@ichorms.com
Los
Gerrit
G
Lin
Xinjian
X
Kurdi-Haidar
Buran
B
Manorek
Gerald
G
Howell
Stephen B
SB
D000595:Amino Acid Sequence; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013866:Thioguanine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D013866:Thioguanine