HUMAN MUTS-ALPHA SPECIFICALLY BINDS TO DNA CONTAINING AMINOFLUORENE AND ACETYLAMINOFLUORENE ADDUCTS

Defects in mismatch repair are associated with several types of cancer . It is also generally believed that environmental carcinogens are res ponsible for the initiation of cancers by the induction of mutations i n critical genes. Prior genetic studies have suggested that the mismat ch repair system can also recognize certain forms of DNA damage such a s O-6-methylguanine and UV photoproducts, and, therefore, mismatch rep air may play a role in environmental agent-induced carcinogenesis. To examine this hypothesis, hMutS alpha, a heterodimer which consists of hMSH2 and GTBP and participates in strand specific mismatch repair, wa s tested for its ability to recognize DNA containing a site specific C -8-guanine adduct of aminofluorene (AF) or N-acetyl-2-aminofluorene (A AF). We show here that hMutS alpha specifically binds to both AF and A AF adducts. This binding requires both hMSH2 and GTBP. Results from co mpetition and titration experiments indicate that the binding efficien cy of hMutS alpha to AF and AAF is about 60% of that to a G-T mismatch , but is at least 10-fold that to an otherwise identical homoduplex DN A without the chemical modification. The specific binding of AF and AA F adducts by hMutS alpha suggests that strand-specific mismatch repair is involved in processing DNA damage induced by environmental carcino gens.