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Molecular and Cellular Biology, August 2007, p. 5587-5596, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.01883-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The E295K DNA Polymerase Beta Gastric Cancer-Associated Variant Interferes with Base Excision Repair and Induces Cellular Transformation ^,

Tieming Lang, Shibani Dalal, Anna Chikova, Daniel DiMaio, and Joann B. Sweasy^*

Departments of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut

Received 5 October 2006/ Returned for modification 17 November 2006/ Accepted 14 May 2007

Approximately 30% of human tumors examined for mutations in polymerase beta (pol ß) appear to express pol ß variant proteins (D. Starcevic, S. Dalal, and J. B. Sweasy, Cell Cycle 3:998-1001, 2004). Many of these variants result from a single amino acid substitution. We have previously shown that the K289M and I260M colon and prostate cancer variants, respectively, induce cellular transformation most likely due to sequence-specific mutator activity (S. Dalal et al., Biochemistry 44:15664-15673, 2005; T. Lang et al., Proc. Natl. Acad. Sci. USA 101:6074-6079, 2004; J. B. Sweasy et al., Proc. Natl. Acad. Sci. USA 102:14350-14355, 2005). In the work described here, we show that the E295K gastric carcinoma pol ß variant acts in a dominant-negative manner by interfering with base excision repair. This leads to an increase in sister chromatid exchanges. Expression of the E295K variant also induces cellular transformation. Our data suggest that unfilled gaps are channeled into a homology-directed repair pathway that could lead to genomic instability. The results indicate that base excision repair is critical for maintaining genome stability and could therefore be a tumor suppressor mechanism.

Published ahead of print on 25 May 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Authors contributed equally to this work.

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