Nucleic Acids Research Advance Access originally published online on May 24, 2008
Nucleic Acids Research 2008 36(11):3847-3856; doi:10.1093/nar/gkn310
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Nucleic Acids Research, 2008, Vol. 36, No. 11 3847-3856
© 2008 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 |
Low-fidelity DNA synthesis by human DNA polymerase theta
1Laboratory of Molecular Genetics and Laboratory of Structural Biology, NIEHS, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, 2Department of Pharmacology, University of Pittsburgh Medical School, Hillman Cancer Center, Research Pavilion Suite 2.6, 5117 Centre Avenue, Pittsburgh, PA 15213-1863 and 3National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20894, USA
*To whom correspondence should be addressed. Tel: +1 919 541 2644; Fax: +1 919 541 7613; Email: kunkel{at}niehs.nih.gov
Received March 18, 2008. Revised April 28, 2008. Accepted April 30, 2008.
Human DNA polymerase theta (pol 
or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol may synthesize DNA with low fidelity. Here, we show that when copying undamaged DNA, pol generates single base errors at rates 10- to more than 100-fold higher than for other family A members. Pol adds single nucleotides to homopolymeric runs at particularly high rates, exceeding 1% in certain sequence contexts, and generates single base substitutions at an average rate of 2.4 x 10–3, comparable to inaccurate family Y human pol 
(5.8 x 10–3) also implicated in TLS. Like pol , pol is processive, implying that it may be tightly regulated to avoid deleterious mutagenesis. Pol also generates certain base substitutions at high rates within sequence contexts similar to those inferred to be copied by pol during SHM of immunoglobulin genes in mice. Thus, pol is an exception among family A polymerases, and its low fidelity is consistent with its proposed roles in TLS and SHM.
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