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Nucleic Acids Research Advance Access originally published online on November 26, 2007
Nucleic Acids Research 2008 36(2):411-422; doi:10.1093/nar/gkm1053
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Nucleic Acids Research, 2008, Vol. 36, No. 2 411-422
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acid Enzymes

The Leu22Pro tumor-associated variant of DNA polymerase beta is dRP lyase deficient

Shibani Dalal1, Anna Chikova1, Joachim Jaeger2 and Joann B. Sweasy1,*

1Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520 and 2The Center for Medical Sciences, Wadsworth Center/NYS-DOH, Albany, New York 12201-0509, USA

*To whom correspondence should be addressed: Tel: +1 203 737 2626; Fax: +1 203 785 6309; Email: joann.sweasy{at}yale.edu

Received July 25, 2007. Revised October 16, 2007. Accepted November 7, 2007.

Approximately 30% of human tumors characterized to date express DNA polymerase beta (pol β) variant proteins. Two of the polymerase beta cancer-associated variants are sequence-specific mutators, and one of them binds to DNA but has no polymerase activity. The Leu22Pro (L22P) DNA polymerase beta variant was identified in a gastric carcinoma. Leu22 resides within the 8 kDa amino terminal domain of DNA polymerase beta, which exhibits dRP lyase activity. This domain catalyzes the removal of deoxyribose phosphate during short patch base excision repair. We show that this cancer-associated variant has very little dRP lyase activity but retains its polymerase activity. Although residue 22 has no direct contact with the DNA, we report here that the L22P variant has reduced DNA-binding affinity. The L22P variant protein is deficient in base excision repair. Molecular dynamics calculations suggest that alteration of Leu22 to Pro changes the local packing, the loop connecting helices 1 and 2 and the overall juxtaposition of the helices within the N-terminal domain. This in turn affects the shape of the binding pocket that is required for efficient dRP lyase catalysis.


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