Active site mutations in mammalian DNA polymerase delta alter accuracy and replication fork progression.

The Journal of Biological Chemistry
Michael W SchmittLawrence A Loeb

Abstract

DNA polymerase δ (pol δ) is one of the two main replicative polymerases in eukaryotes; it synthesizes the lagging DNA strand and also functions in DNA repair. In previous work, we demonstrated that heterozygous expression of the pol δ L604G variant in mice results in normal life span and no apparent phenotype, whereas a different substitution at the same position, L604K, is associated with shortened life span and accelerated carcinogenesis. Here, we report in vitro analysis of the homologous mutations at position Leu-606 in human pol δ. Four-subunit human pol δ variants that harbor or lack 3' → 5'-exonucleolytic proofreading activity were purified from Escherichia coli. The pol δ L606G and L606K holoenzymes retain catalytic activity and processivity similar to that of wild type pol δ. pol δ L606G is highly error prone, incorporating single noncomplementary nucleotides at a high frequency during DNA synthesis, whereas pol δ L606K is extremely accurate, with a higher fidelity of single nucleotide incorporation by the active site than that of wild type pol δ. However, pol δ L606K is impaired in the bypass of DNA adducts, and the homologous variant in mouse embryonic fibroblasts results in a decreased rate of replication fork progr...Continue Reading

References

Dec 25, 1984·Journal of Molecular Biology·D T Weaver, M L DePamphilis
Jan 1, 1995·Methods in Enzymology·K Bebenek, T A Kunkel
Jan 1, 1996·Annual Review of Biochemistry·P Modrich, R Lahue
Aug 8, 1997·The Journal of Biological Chemistry·K B Beckman, B N Ames
Jul 25, 1998·The Journal of Biological Chemistry·P M Burgers, K J Gerik
Jan 27, 2000·Cell·D Hanahan, R A Weinberg
Aug 31, 2000·Annual Review of Biochemistry·T A Kunkel, K Bebenek
Nov 9, 2000·The Journal of Biological Chemistry·P H PatelL A Loeb
Oct 17, 2001·The Journal of Biological Chemistry·A Shinkai, L A Loeb
May 3, 2002·The Journal of Biological Chemistry·Xiaoqing LuAntero G So
May 4, 2002·Nature Reviews. Molecular Cell Biology·Igor V Shevelev, Ulrich Hübscher
Nov 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Robert E GoldsbyBradley D Preston
May 10, 2003·Structure·William A Beard, Samuel H Wilson
Jun 28, 2003·Journal of Cell Science·Giovanni Maga, Ulrich Hubscher
Apr 2, 2004·The EMBO Journal·Eva FreisingerCaroline Kisker
Dec 1, 2004·Annual Review of Genetics·Deborah E Barnes, Tomas Lindahl
Dec 14, 2005·The Journal of Biological Chemistry·Ranga N VenkatesanLawrence A Loeb
Apr 21, 2006·The FEBS Journal·Jung-Suk Sung, Bruce Demple
Jul 4, 2006·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Christopher K Mathews
Aug 15, 2006·The Journal of Biological Chemistry·Paul Modrich
Sep 13, 2006·Proceedings of the National Academy of Sciences of the United States of America·Robert A Beckman, Lawrence A Loeb
Oct 28, 2006·Radiation Research·Joann B SweasyKristin A Eckert
Nov 17, 2006·Proceedings of the National Academy of Sciences of the United States of America·Jason H BielasLawrence A Loeb
Feb 16, 2007·The Journal of Biological Chemistry·Ern LohLawrence A Loeb
Mar 3, 2007·Trends in Genetics : TIG·Jason H BielasLawrence A Loeb
Mar 6, 2007·Nature Genetics·Marc VermulstLawrence A Loeb
Mar 9, 2007·Nature·Christopher GreenmanMichael R Stratton
Mar 4, 2008·Nature Genetics·Marc VermulstLawrence A Loeb
Jul 16, 2008·Nature Reviews. Genetics·Lawrence A Loeb, Raymond J Monnat
Oct 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Rebecca J LearyVictor E Velculescu
Jan 14, 2009·Proceedings of the National Academy of Sciences of the United States of America·Lisiane B MeiraLeona D Samson
Mar 14, 2009·Nucleic Acids Research·Ruzaliya FazlievaYoshihiro Matsumoto
Apr 16, 2009·Cellular and Molecular Life Sciences : CMLS·Caixia GuoErrol C Friedberg
May 5, 2009·Biochimica Et Biophysica Acta·Laura C Greaves, Doug M Turnbull
Jun 11, 2009·Cancer Research·Edward J FoxLawrence A Loeb
Jun 23, 2009·Biochimie·Michael W SchmittLawrence A Loeb
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Tina M AlbertsonBradley D Preston
Dec 18, 2009·Nature·Erin D PleasanceMichael R Stratton
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Ern LohLawrence A Loeb

❮ Previous
Next ❯

Citations

May 20, 2011·Nature Reviews. Cancer·Lawrence A Loeb
Aug 3, 2012·Proceedings of the National Academy of Sciences of the United States of America·Michael W SchmittLawrence A Loeb
Feb 3, 2015·Nature Genetics·Adam ShlienUNKNOWN Biallelic Mismatch Repair Deficiency Consortium
Oct 8, 2011·Critical Reviews in Biochemistry and Molecular Biology·Alan J HerrBradley D Preston
Oct 16, 2012·Environmental and Molecular Mutagenesis·Marc J Prindle, Lawrence A Loeb
Jan 7, 2014·Genetics·Alan J HerrBradley D Preston
Sep 23, 2014·Nature Communications·Medini Manohar GhodgaonkarJosef Jiricny
Sep 8, 2012·Annals of the New York Academy of Sciences·Michael W SchmittLawrence A Loeb

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.