Gm. Li et al., HUMAN MUTS-ALPHA SPECIFICALLY BINDS TO DNA CONTAINING AMINOFLUORENE AND ACETYLAMINOFLUORENE ADDUCTS, The Journal of biological chemistry, 271(39), 1996, pp. 24084-24088
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.