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Nucleic Acids Research Advance Access originally published online on December 11, 2008
Nucleic Acids Research 2009 37(2):647-657; doi:10.1093/nar/gkn1000
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Nucleic Acids Research, 2009, Vol. 37, No. 2 647-657
© 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.

Genome integrity, repair and replication

DNA damage alters DNA polymerase {delta} to a form that exhibits increased discrimination against modified template bases and mismatched primers

Xiao Meng, Yajing Zhou, Sufang Zhang, Ernest Y. C. Lee, David N. Frick and Marietta Y. W. T. Lee*

Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA

*To whom correspondence should be addressed. Tel: +1 914 594 4070; Fax: +1 914 594 4058; Email: Marietta_Lee{at}NYMC.edu

Received October 23, 2008. Revised November 25, 2008. Accepted November 26, 2008.

Human DNA polymerase {delta} (Pol {delta}4), a key enzyme in chromosomal replication, is a heterotetramer composed of the p125, p50, p68 and p12 subunits. Genotoxic agents such as UV and alkylating chemicals trigger a DNA damage response in which Pol {delta}4 is converted to a trimer (Pol {delta}3) by degradation of p12. We show that Pol {delta}3 has altered enzymatic properties: it is less able to perform translesion synthesis on templates containing base lesions (O6-MeG, 8-oxoG, an abasic site or a thymine-thymine dimer); a greater proofreading activity; an increased exonuclease/polymerase activity ratio; a decreased tendency for the insertion of wrong nucleotides, and for the extension of mismatched primers. Overall, our findings indicate that Pol {delta}3 exhibits an enhanced ability for the detection of errors in both primers and templates over its parent enzyme. These alterations in Pol {delta}3 show that p12 plays a major role in Pol {delta}4 catalytic functions, and provides significant insights into the rationale for the conversion of Pol {delta}4 to Pol {delta}3 in the cellular response to DNA damage.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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