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The E295K DNA polymerase beta gastric cancer-associated variant interferes with base excision repair and induces

Tieming Lang1, Shibani Dalal, Anna Chikova

  • 1Department of Therapeutic Radiology, Yale University School of Medicine, 15 York Street, P.O. Box 20840, New Haven, CT 06520, USA.

Molecular and Cellular Biology
|May 29, 2007
PubMed

Insights

Polymerase beta (pol beta) variants in human tumors can cause cellular transformation. The E295K variant disrupts base excision repair, increasing genomic instability and suggesting a tumor suppressor role for this repair pathway.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Approximately 30% of human tumors harbor mutations in polymerase beta (pol beta).
  • Several pol beta variants, resulting from single amino acid substitutions, are expressed in human cancers.
  • Previously identified K289M and I260M variants induce cellular transformation via mutator activity.

Purpose of the Study:

  • To investigate the functional impact of the E295K gastric carcinoma pol beta variant.
  • To determine the mechanism by which the E295K variant affects DNA repair and genome stability.

Main Methods:

  • Expression of the E295K pol beta variant in cells.
  • Assessment of base excision repair (BER) activity.
  • Analysis of sister chromatid exchanges (SCEs).
  • Evaluation of cellular transformation and DNA repair pathway channeling.

Main Results:

  • The E295K pol beta variant acts in a dominant-negative manner, inhibiting base excision repair.
  • Expression of E295K leads to a significant increase in sister chromatid exchanges.
  • The E295K variant induces cellular transformation.
  • Unfilled DNA gaps appear to be rerouted to homology-directed repair, promoting genomic instability.

Conclusions:

  • Base excision repair is crucial for maintaining genome stability.
  • Disruption of BER by pol beta variants can lead to genomic instability and potentially contribute to tumorigenesis.
  • BER pathway functions as a tumor suppressor mechanism.

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