A novel R229Q OGG1 polymorphism results in a thermolabile enzyme that sensitizes KG-1 leukemia cells to DNA damaging agents.

Abstract

BACKGROUND:

Mutations and polymorphisms of OGG1, the major mammalian 8-oxoguanine repair activity, are associated with increased risk for several cancers. Decreased 8-oxoguanine repair capacity due to variant forms of the OGG1 gene is a common feature of numerous cancer cell lines. One such cell line, human KG-1 leukemia cells, has previously been demonstrated to be deficient in the excision of 8-oxoguanine from oxidatively damaged DNA. KG-1 cells have a homozygous R229Q amino acid substitution in OGG1 that has been presumed to alter the function of OGG1 and result in elevated levels of genomic 8-oxoG and hypersensitivity to 8-hydroxydeoxyguanosine nucleoside and ionizing radiation observed in KG-1 cells.

METHODS:

We characterized the enzymatic activity of R229Q OGG1 and the effect of the enzyme on cell survival following treatment with DNA damaging agents.

RESULTS:

R229Q OGG1 had activity similar to the wild-type enzyme, yet was easily heat inactivated at physiological temperature. R229Q OGG1 expressed in human cells had significantly lower activity than wild-type OGG1 and was also highly thermolabile. Expression of R229Q OGG1 sensitized KG-1 cells to killing by menadione and 8-hydroxydeoxyguanosine, but not ionizing radiation.

CONCLUSIONS:

These results suggest that decreased 8-oxoguanine repair in KG-1 is due to thermolability of R229Q OGG1 and that the enzyme variant increases cellular susceptibility to killing resulting from oxidative DNA damage. The R229Q OGG1 variant is a validated polymorphism prevalent in world populations and not an isolated mutation in KG-1 cells, thus the R229Q OGG1 allele may be a novel marker for cancer susceptibility.

• Authors: Jeff W Hill, Michele K Evans
• Journal: Cancer detection and prevention (Cancer Detect Prev) Vol. 31 Issue 3 Pg. 237-43 ( 2007) ISSN: 0361-090X [Print] England
• PMID: 17651912 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Vitamins
• 8-hydroxyguanine
• Guanine
• Vitamin K 3
• 8-Hydroxy-2'-Deoxyguanosine
• DNA Glycosylases
• oxoguanine glycosylase 1, human
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Alleles
• Amino Acid Substitution
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics, radiation effects)
• DNA Damage (drug effects, radiation effects)
• DNA Glycosylases (genetics, metabolism)
• Deoxyguanosine (analogs & derivatives, pharmacology)
• Gene Expression
• Guanine (analogs & derivatives, metabolism)
• Hot Temperature
• Humans
• Leukemia (enzymology, genetics, therapy)
• Polymorphism, Genetic
• Radiation, Ionizing
• Vitamin K 3 (pharmacology)
• Vitamins (pharmacology)