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Nucleic Acids Research, 1995, Vol. 23, No. 9 1597-1603
© 1995

ENZYMOLOGY

Specific inhibition of DNA polymerase ß by its 14 kDa domain: role of single- and double-stranded DNA binding and 5'-phosphate recognition

Intisar Husain, Bradley S. Morton, William A. Beard1, Rakesh K. Singhal1, Rajendra Prasad1, Samuel H. Wilson1 and Jeffrey M. Besterman*

Department of Cell Biology, Glaxo Research Institute Research Triangle Park, NC 27709, USA 1Sealy Center for Molecular Science, University of Texas Medical Branch Galveston, TX 77555-1068, USA

* To whom correspondence should be addressed

Received November 30, 1994. Revised March 20, 1995. Accepted March 20, 1995.

DNA polymerase ß(ß-polymerase) has been implicated in short-patch DNA synthesis In the DNA repair pathway known as base excision repair. The native 39 kDa enzyme is organized into four structurally and functionally distinct domains. In an effort to examine this enzyme as a potential therapeutic target, we analyzed the effect of various ß-polymerase domains on the activity of the enzyme in vitro. We show that the 14 kDa N-terminal segment of ß-polymerase, which binds to both single- and double-stranded DNA, but lacks DNA polymerase activity, inhibits ß-polymerase activity In vitro. Most importantly, the 8, 27 and 31 kDa domains of ß-polymerase do not Inhibit ß-polymerase activity, demonstrating that the inhibition by the 14 kDa domain is specific. The inhibition of ß-polymerase activity in vitro is abolished by Increasing the concentrations of both of the substrates (template-primer and deoxynucleoside triphosphate). In contrast, an In vitro base excision repair assay is inhibited in a domain specific manner by the 14 kDa domain even in the presence of saturating substrates. The inhibition of ß-polymerase activity by the 14 kDa domain appears specific to ß-polymerase as this domain does not inhibit either mammalian DNA polymerase {alpha} or Es-cherlchia coll polymerase I (Klenow fragment). These data suggest that the 14 kDa domain could be used as a potential inhibitor of intracellular ß-polymerase and that it may provide a means for sensitizing cells to therapeutically relevant DNA damaging agents.


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