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DNA glycosylases

Friday 27 May 2005

DNA glycosylases remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase).

Functions

Reactive oxygen species from endogenous and environmental sources induce oxidative damage to DNA, and hence pose an enormous threat to the genetic integrity of cells.

Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation and other by-products of cellular metabolism. The BER system is initiated by DNA glycosylases, that simply remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase).

Active oxygen species in the nucleotide pool of the cell can produce 8-oxo-dGTP (8-oxo-7,8-dihydrodeoxyguanosine triphosphate), which can then be incorporated into cellular DNA. Human cells contain enzyme activity that hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby preventing occurrence of mutations caused by misincorporation.

This oxidative DNA damage is restored by the base excision repair (BER) pathway that is conserved from bacteria to humans and is initiated by DNA glycosylases, which simply remove the aberrant base from the DNA backbone by hydrolyzing the N-glycosidic bond (monofunctional DNA glycosylase), or further catalyze the incision of a resulting abasic site (bifunctional DNA glycosylase).

Members

MPG MUTYH MPG OGG1 SMUG1 TDG UNG

Functions

In human cells, oxidative pyrimidine lesions are generally removed by NTHL1 (NTH1), NEIL1, or NEIL2, whereas oxidative purine lesions are removed by hOGG1. SMUG1 excises a subset of oxidative base damage that is poorly recognized by the above enzymes.

Unlike these enzymes, MUTYH (hMYH) removes intact A misincorporated opposite template 8-oxoguanine during DNA replication.

- Although hNTH1, hOGG1, and hMYH account for major cellular glycosylase activity for inherent substrate lesions, mouse models deficient in the enzymes exhibit no overt phenotypes such as the development of cancer, implying backup mechanisms.

- Contrary to the mouse model, hMYH mutations have been shown to lead to a multiple colorectal adenoma syndrome and high colorectal cancer risk.

- Oxidative pyrimidine lesions are generally removed by hNTH1, hNEIL1, or hNEIL2, whereas oxidative purine lesions are removed by hOGG1. hSMUG1 excises a subset of oxidative base damage that is poorly recognized by the above enzymes.
Unlike other DNA glycosylases, hMYH removes intact a misincorporated opposite template 8-oxoguanine during DNA replication. hMYH mutations have been shown to lead to a multiple colorectal adenoma syndrome and high colorectal cancer risk.

- For cleavage of the N-glycosidic bond, bifunctional DNA glycosylases (hNTH1, hNEIL1, hNEIL2, and hOGG1) use Lys or Pro for direct attack on sugar C1’, whereas monofunctional DNA glycosylases (hSMUG1 and hMYH) use an activated water molecule.

- DNA glycosylases for oxidative damage, if not all, are covalently trapped by DNA containing 2-deoxyribonolactone or oxanine. Thus, the depletion of functional DNA glycosylases using covalent trapping may reduce the BER capacity of cancer cells, hence potentiating the efficacy of anticancer drugs or radiation therapy.

Pathology

- UNG: mutations in type 5 hyper-IgM syndrome (HIGM5) (MIM.608106)
- OGG1: mutations in clear cell renal cell carcinoma (MIM.144700)
- MUTYH: mutations in

  • autosomal recessive colorectal adenomatous polyposis (MIM.608456)
  • sporadic gastric carcinoma (MIM.137215)
  • association pilomatrixoma/colorectal adenomatous polyposis

References

- Ide H, Kotera M. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol Pharm Bull. 2004 Apr;27(4):480-5. PMID: 15056851

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