Abstract
Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. DNA glycosylases recognize and remove specific lesions in the first step of BER. The existence of a number of these enzymes with overlapping substrate specificities has been thought to be the reason why single knock-out models of individual DNA glycosylases are not cancer prone. In this work we have characterized DNA glycosylases NEIL1 and NEIL2 (Neil1−/−/Neil2−/−) double and NEIL1, NEIL2 and NEIL3 (Neil1−/−/Neil2−/−/Neil3−/−) triple knock-out mouse models. Unexpectedly, our results show that these mice are not prone to cancer and have no elevated mutation frequencies under normal physiological conditions. Moreover, telomere length is not affected and there was no accumulation of oxidative DNA damage compared to wild-type mice. These results strengthen the hypothesis that the NEIL enzymes are not simply back-up enzymes for each other but enzymes that have distinct functions beyond canonical repair.
Highlights
Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention
Six mammalian DNA glycosylases initiate BER of a broad spectrum of oxidative DNA base lesions: E. coli Nei endonuclease VIII-like (NEIL) NEIL1, NEIL2 and NEIL3, 8-oxoguanine DNA glycosylase (OGG1), Escherichia coli (E. coli) MutY homologue (MUTYH) and E. coli Nth endonuclease III-like 1 (NTHL1)19, 20. 8-oxo-7,8-dihydroguanine (8-oxoG) is a major DNA oxidized lesion removed by OGG121, 22
The results presented in this paper strongly indicate that the NEIL DNA glycosylases are not back-up enzymes for each other in processing of oxidized DNA bases
Summary
Base excision repair (BER) is a major pathway for removal of DNA base lesions and maintenance of genomic stability, which is essential in cancer prevention. While deficiency of the common downstream enzymes of BER and the thymine-DNA glycosylase (TDG/ Tdg) are embryonic lethal, the remaining DNA glycosylase-deficient mouse models have failed to display elevated mutation rates, increased cancer incidence or other severe phenotypes in the absence of any mutagenic insult[34,35,36,37,38,39,40]. This lack of altered phenotype exhibited by the single DNA glycosylase-deficient models has been ascribed to redundancy, or so-called back-up activities, between the enzymes as well as repair by alternative repair pathways
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