Abstract |
DNA polymerase beta (Pol beta) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol beta variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol beta and proliferating cell nuclear antigen ( PCNA). These defects impair the DNA repair capacity of Pol beta in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol beta in pol beta(-/-) mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol beta(-/-) MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers.
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Authors | Zhigang Guo, Li Zheng, Huifang Dai, Mian Zhou, Hong Xu, Binghui Shen |
Journal | Nucleic acids research
(Nucleic Acids Res)
Vol. 37
Issue 10
Pg. 3431-41
(Jun 2009)
ISSN: 1362-4962 [Electronic] England |
PMID | 19336415
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Proliferating Cell Nuclear Antigen
- Glutamine
- Arginine
- DNA Polymerase beta
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Topics |
- Amino Acid Substitution
- Animals
- Arginine
(genetics)
- Cells, Cultured
- DNA Damage
- DNA Polymerase beta
(genetics, metabolism)
- DNA Repair
- Gene Knockout Techniques
- Glutamine
(genetics)
- Humans
- Mice
- Polymorphism, Single Nucleotide
- Proliferating Cell Nuclear Antigen
(metabolism)
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