Published online 28 June 2006
© 2006 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-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Promiscuous mismatch extension by human DNA polymerase lambda
1 Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), Universidad Autónoma 28049 Madrid, Spain 2 Laboratory of Molecular Genetics, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park NC 27709, USA 3 Laboratory of Structural Biology, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park NC 27709, USA
*To whom correspondence should be addressed. Tel: +34 91 4978493; Fax: +34 91 4974799; Email: lblanco{at}cbm.uam.es
Received February 2, 2006. Revised April 6, 2006. Accepted April 30, 2006.
DNA polymerase lambda (Pol 
) is one of several DNA polymerases suggested to participate in base excision repair (BER), in repair of broken DNA ends and in translesion synthesis. It has been proposed that the nature of the DNA intermediates partly determines which polymerase is used for a particular repair reaction. To test this hypothesis, here we examine the ability of human Pol to extend mismatched primer-termini, either on ‘open’ template-primer substrates, or on its preferred substrate, a 1 nt gapped-DNA molecule having a 5'-phosphate. Interestingly, Pol extended mismatches with an average efficiency of 
10–2 relative to matched base pairs. The match and mismatch extension catalytic efficiencies obtained on gapped molecules were 260-fold higher than on template-primer molecules. A crystal structure of Pol in complex with a single-nucleotide gap containing a dG·dGMP mismatch at the primer-terminus (2.40 Å) suggests that, at least for certain mispairs, Pol is unable to differentiate between matched and mismatched termini during the DNA binding step, thus accounting for the relatively high efficiency of mismatch extension. This property of Pol suggests a potential role as a ‘mismatch extender’ during non-homologous end joining (NHEJ), and possibly during translesion synthesis.
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