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Originally published In Press as doi:10.1074/jbc.M106336200 on July 16, 2001

J. Biol. Chem., Vol. 276, Issue 37, 34659-34663, September 14, 2001
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Identification of an Intrinsic 5'-Deoxyribose-5-phosphate Lyase Activity in Human DNA Polymerase lambda
A POSSIBLE ROLE IN BASE EXCISION REPAIR*

Miguel García-DíazDagger §, Katarzyna Bebenek§, Thomas A. Kunkel, and Luis BlancoDagger ||

From the Dagger  Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma, 28049 Madrid, Spain and the  Laboratory of Molecular Genetics, NIEHS, Research Triangle Park, North Carolina 27709

Base excision repair (BER) is a major repair pathway in eukaryotic cells responsible for repair of lesions that give rise to abasic (AP) sites in DNA. Pivotal to this process is the 5'-deoxyribose-5-phosphate lyase (dRP lyase) activity of DNA polymerase beta  (Pol beta ). DNA polymerase lambda  (Pol lambda ) is a recently identified eukaryotic DNA polymerase that is homologous to Pol beta . We show here that human Pol lambda  exhibits dRP lyase, but not AP lyase, activity in vitro and that this activity is consistent with a beta -elimination mechanism. Accordingly, a single amino acid substitution (K310A) eliminated more than 90% of the wild-type dRP lyase activity, thus suggesting that Lys310 of Pol lambda  is the main nucleophile involved in the reaction. The dRP lyase activity of Pol lambda , in coordination with its polymerization activity, efficiently repaired uracil-containing DNA in an in vitro reconstituted BER reaction. These results suggest that Pol lambda  may participate in "single-nucleotide" base excision repair in mammalian cells.

* This work was supported by Dirección General de Ense<OVL>n</OVL>anza Superior Grant PB97-1192, Comunidad Autónoma de Madrid Grants 08.1/0044/98 and 08.5/0063/2000 (to L. B.), and by an institutional grant from Fundación Ramón Areces.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| To whom correspondence should be addressed: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Campus de la Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. E-mail: lblanco@cbm.uam.es.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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