Human MutY: gene structure,protein functions and interactions,and role in carcinogenesis

Faithful maintenance of the genome is crucial to the individual and the species. Oxidative DNA damage, such as 8-oxo-7,8-dihydroguanine (8-oxoG), poses a major threat to genomic integrity. 8-OxoG can mispair with 2-deoxycytidine 5-triphosphate or with 2-deoxyadenosine triphosphate during DNA replication, forming C8-oxoG and A8-oxoG mispairs. Human MutY is responsible for recognition and removal of the inappropriately inserted adenine in an A8-oxoG mispair. If unrepaired, the A8-oxoG mispairs can result in deleterious C:G to A:T transversions. Human MutY functions in a postreplication repair pathway and is targeted to the newly synthesized daughter strand of DNA for removal of the adenine base. The human MutY protein is targeted to both the mitochondria and the nucleus and associates with the proliferating cell nuclear antigen, apurinic/ apyrimidinic endonuclease 1, replication protein A and mutS homolog 6 proteins. Mutations in the human MutY gene and defective activity of the human MutY protein have been detected in cancer. A direct correlation between defective A8-oxoG repair and increased levels of genomic 8-oxoG has now been established.Received 10 February 2003; received after revision 7 April 2003; accepted 14 April 2003