Nucleic Acids Research Advance Access originally published online on March 31, 2009
Nucleic Acids Research 2009 37(10):3431-3441; doi:10.1093/nar/gkp201
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Nucleic Acids Research, 2009, Vol. 37, No. 10 3431-3441
© 2009 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 |
Human DNA polymerase β polymorphism, Arg137Gln, impairs its polymerase activity and interaction with PCNA and the cellular base excision repair capacity
Department of Radiation Biology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010, USA
*To whom correspondence should be addressed. Tel: +1 626 301 8879; Fax: +1 626 301 8280; Email: bshen{at}coh.org
Received December 28, 2008. Revised March 9, 2009. Accepted March 10, 2009.
DNA polymerase β (Pol β) is a key enzyme in DNA base excision repair, and an important factor for maintaining genome integrity and stability. More than 30% of human tumors characterized to date express DNA Pol β variants, many of which result from a single nucleotide residue substitution. However, in most cases, their precise functional deficiency and relationship to cancer susceptibility are still unknown. In the current work, we show that a polymorphism encoding an arginine to glutamine substitution, R137Q, has lower polymerase activity. The substitution also affects the interaction between Pol β and proliferating cell nuclear antigen (PCNA). These defects impair the DNA repair capacity of Pol β in reconstitution assays, as well as in cellular extracts. Expression of wild-type Pol β in pol β–/– mouse embryonic fibroblast (MEF) cells restored cellular resistance to DNA damaging reagents such as methyl methanesulfonate (MMS) and N-methyl-N-nitrosourea (MNU), while expression of R137Q in pol β–/– MEF cells failed to do so. These data indicate that polymorphisms in base excision repair genes may contribute to the onset and development of cancers.