Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes

DNA damage of endogenous origin may significantly contribute to human cance r. A major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER). BER is rather efficient in human cells but a certain amount of endogenous damage inevitably escapes mending and likely contribu tes to human carcinogenesis. Apart from some glycosylases that are particul arly sluggish (e.g. 8-oxoG DNA glycosylase), recent work suggests that the general rate-limiting steps of BER may be trimming of 2-deoxyribose 5-phosp hate in case the process is started by a monofunctional glycosylase or trim ming of a 3'-blocking fragment, in case BER is started by a bifunctional gl ycosylase or in the case of single-strand breaks produced by free radical a ttack. Overexpression of the 5'-deoxyribophosphodiesterase (dRPase) domain of DNA polymerase beta, on the one hand, and of yeast APN1 protein, contain ing an efficient 3' repair activity, on the other, may lead to improved BER in mammals. The recently characterized S3 protein of Drosophila, containin g both dRPase and 3'-trimming activities, could also be considered for over expression studies. The possible protecting role of enhanced BER could be i nvestigated in cultured rodent embryonic fibroblasts undergoing spontaneous transformation, a most interesting system that merits rediscovery.