Nucleic Acids Research Advance Access originally published online on September 8, 2006
Nucleic Acids Research 2006 34(16):4572-4582; doi:10.1093/nar/gkl457
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Nucleic Acids Research, 2006, Vol. 34, No. 16 4572-4582
© 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-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
A specific loop in human DNA polymerase mu allows switching between creative and DNA-instructed synthesis
Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), Campus Universidad Autónoma Canto Blanco, 28049 Madrid, Spain 1 Lineberger Comprehensive Cancer Center and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill NC 27599, USA
*To whom correspondence should be addressed at Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), Universidad Autónoma, 28049 Madrid, Spain. Tel: +34 91 4978493; Fax: +34 91 4974799; Email: lblanco{at}cbm.uam.es
Received April 5, 2006. Revised May 8, 2006. Accepted May 10, 2006.
Human DNA polymerase mu (Polµ) is a family X member that has terminal transferase activity but, in spite of a non-orthodox selection of the template information, displays its maximal catalytic efficiency in DNA-templated reactions. As terminal deoxynucleotidyl transferase (TdT), Polµ has a specific loop (loop1) that could provide this enzyme with its terminal transferase activity. When loop1 was deleted, human Polµ lacked TdT activity but improved DNA-binding and DNA template-dependent polymerization. Interestingly, when loop1 from TdT was inserted in Polµ (substituting its cognate loop1), the resulting chimaera displayed TdT activity, preferentially inserting dGTP residues, but had a strongly reduced template-dependent polymerization activity. Therefore, a specialized loop in Polµ, that could adopt alternative conformations, appears to provide this enzyme with a dual capacity: (i) template independency to create new DNA information, in which loop1 would have an active role by acting as a ‘pseudotemplate’; (ii) template-dependent polymerization, in which loop1 must allow binding of the template strand. Recent in vivo and in vitro data suggest that such a dual capacity could be advantageous to resolve microhomology-mediated end-joining reactions.
Present address: Stephanie A. Nick McElhinny, Laboratory of Structural Biology and Laboratory of Molecular Genetics. National Institutes of Environmental Health Sciences. NIH, DHHS, Research Triangle Park, NC 27709, USA
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