Journal Article

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

Guido Frosina

in Carcinogenesis

Volume 22, issue 9, pages 1335-1341
Published in print September 2001 | ISSN: 0143-3334
Published online September 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.9.1335
Counteracting spontaneous transformation via overexpression of rate-limiting DNA base excision repair enzymes

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DNA damage of endogenous origin may significantly contribute to human cancer. 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 contributes to human carcinogenesis. Apart from some glycosylases that are particularly 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-phosphate in case the process is started by a monofunctional glycosylase or trimming of a 3′-blocking fragment, in case BER is started by a bifunctional glycosylase or in the case of single-strand breaks produced by free radical attack. Overexpression of the 5′-deoxyribophosphodiesterase (dRPase) domain of DNA polymerase β, on the one hand, and of yeast APN1 protein, containing an efficient 3′ repair activity, on the other, may lead to improved BER in mammals. The recently characterized S3 protein of Drosophila, containing both dRPase and 3′-trimming activities, could also be considered for overexpression studies. The possible protecting role of enhanced BER could be investigated in cultured rodent embryonic fibroblasts undergoing spontaneous transformation, a most interesting system that merits rediscovery.

Keywords: AP, abasic; BER, base excision repair; dRP, 2-deoxyribose 5-phosphate; dRPase, 5′-deoxyribophosphodiesterase; MEF, mouse embryonic fibroblast; MMS, methylmethanesulfonate; 8-oxoG, 8-oxo-7,8-dihydroguanine; PCNA, proliferating cell nuclear antigen; PNK, polynucleotide kinase; pol β, DNA polymerase β; ROI, reactive oxygen intermediate.

Journal Article.  6286 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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