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Human DNA polymerase beta polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the

Zhigang Guo1, Li Zheng, Huifang Dai

  • 1Department of Radiation Biology, City of Hope National Medical Center, Beckman Research Institute, Duarte, CA 91010, USA.

Nucleic Acids Research
|April 2, 2009
PubMed

Insights

A common DNA polymerase beta (Pol beta) variant, R137Q, shows reduced DNA repair activity. This impaired base excision repair may increase cancer susceptibility, highlighting the role of genetic variations in cancer development.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • DNA polymerase beta (Pol beta) is crucial for DNA base excision repair and genome stability.
  • Numerous human tumors exhibit Pol beta variants, often due to single nucleotide substitutions, but their functional impact remains unclear.
  • Understanding these variants is key to deciphering cancer susceptibility.

Purpose of the Study:

  • To investigate the functional consequences of the R137Q polymorphism in DNA Pol beta.
  • To determine the impact of this variant on DNA repair capacity and its relationship to cancer.
  • To assess the role of Pol beta variants in cellular resistance to DNA damage.

Main Methods:

  • Assessed polymerase activity of the R137Q variant.
  • Examined the interaction between R137Q Pol beta and proliferating cell nuclear antigen (PCNA).
  • Utilized reconstituted DNA repair assays and cellular extracts to evaluate repair capacity.
  • Complemented pol beta(-/-) mouse embryonic fibroblast (MEF) cells with wild-type and R137Q Pol beta to assess DNA damage resistance.

Main Results:

  • The R137Q substitution significantly reduced Pol beta polymerase activity.
  • The R137Q variant exhibited altered interaction with PCNA.
  • Impaired DNA repair capacity was observed for R137Q Pol beta in both in vitro and cellular assays.
  • Expression of R137Q Pol beta failed to restore resistance to DNA damaging agents (MMS, MNU) in pol beta(-/-) MEF cells, unlike wild-type Pol beta.

Conclusions:

  • The R137Q polymorphism in DNA Pol beta impairs its enzymatic activity and DNA repair function.
  • Defective base excision repair due to Pol beta variants like R137Q may contribute to cancer development.
  • Genetic variations in DNA repair genes are potential factors in cancer susceptibility and progression.

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