Active site mutation in DNA polymerase gamma associated with progressive external ophthalmoplegia causes error-prone DNA synthesis

The Journal of Biological Chemistry
Mikhail V PonamarevW C Copeland

Abstract

Progressive external ophthalmoplegia (PEO) is a heritable mitochondrial disorder characterized by the accumulation of multiple point mutations and large deletions in mtDNA. Autosomal dominant PEO was recently shown to co-segregate with a heterozygous Y955C mutation in the human gene encoding the sole mitochondrial DNA polymerase, DNA polymerase gamma (pol gamma). Since Tyr-955 is a highly conserved residue critical for nucleotide recognition among family A DNA polymerases, we analyzed the effects of the Y955C mutation on the kinetics and fidelity of DNA synthesis by the purified human mutant polymerase in complex with its accessory subunit. The Y955C enzyme retains a wild-type catalytic rate (k(cat)) but suffers a 45-fold decrease in apparent binding affinity for the incoming nucleoside triphosphate (K(m)). The Y955C derivative is 2-fold less accurate for base pair substitutions than wild-type pol gamma despite the action of intrinsic exonucleolytic proofreading. The full mutator effect of the Y955C substitution was revealed by genetic inactivation of the exonuclease, and error rates for certain mismatches were elevated by 10-100-fold. The error-prone DNA synthesis observed for the Y955C pol gamma is consistent with the accumul...Continue Reading

References

Jan 1, 1992·Annual Review of Biochemistry·D C Wallace
Jan 22, 1991·Biochemistry·S S CarrollS J Benkovic
Oct 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J M ShoffnerD C Wallace
Oct 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·D R JohnsO Hurko
Jan 1, 1995·Methods in Enzymology·K Bebenek, T A Kunkel
Mar 5, 1999·Science·D C Wallace
Apr 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·L A EspositoD C Wallace
Aug 5, 2000·Science·J KaukonenA Suomalainen
Apr 25, 2001·The Journal of Biological Chemistry·S E Lim, W C Copeland

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Citations

Oct 12, 2010·Cellular and Molecular Life Sciences : CMLS·Jeffrey D Stumpf, William C Copeland
May 26, 2005·Gene·Matthew J LongleyWilliam C Copeland
Feb 11, 2003·Analytical Biochemistry·Barbara J MarriageD Moira Glerum
Jun 6, 2003·Current Opinion in Genetics & Development·Massimo ZevianiValerio Carelli
Feb 9, 2006·Chemical Reviews·Maria A GraziewiczWilliam C Copeland
Jan 2, 2008·Cell Research·Scott D McCulloch, Thomas A Kunkel
Jul 20, 2004·Nature Structural & Molecular Biology·Maria A GraziewiczWilliam C Copeland
Nov 8, 2006·Human Molecular Genetics·Sherine S L ChanWilliam C Copeland
Jun 8, 2004·Nucleic Acids Research·Sjoerd WanrooijJohannes N Spelbrink
Feb 16, 2008·Nucleic Acids Research·Zachary F PursellThomas A Kunkel
Mar 12, 2010·The Neurologist·Margherita Milone, Rami Massie
Jun 11, 2004·Annual Review of Biochemistry·Laurie S Kaguni
Sep 26, 2007·Annual Review of Medicine·William C Copeland
May 9, 2003·Pediatric Research·Orly Elpeleg
Feb 27, 2007·PLoS Genetics·Gregory C KujothTomas A Prolla
Mar 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Shiwei SongChristopher K Mathews
Mar 17, 2010·Methods : a Companion to Methods in Enzymology·Jan-Willem TaanmanThierry Letellier
Feb 24, 2010·Methods : a Companion to Methods in Enzymology·Rajesh KasiviswanathanWilliam C Copeland
Jan 5, 2010·Methods : a Companion to Methods in Enzymology·Christopher KoczorWilliam Lewis
Apr 1, 2005·American Journal of Medical Genetics. Part a·Fuki M HisamaSalvatore DiMauro
Jun 8, 2006·Environmental and Molecular Mutagenesis·James J Kohler, William Lewis
Sep 8, 2010·Developmental Disabilities Research Reviews·Russell P Saneto, Robert K Naviaux
Feb 15, 2005·Neurobiology of Aging·Antonella CormioPalmiro Cantatore
Feb 24, 2006·Mutation Research·Weiming ZhengWilliam C Copeland
May 16, 2013·Parkinsonism & Related Disorders·Masako MukaiShiro Matsubara
Apr 12, 2016·Current Opinion in Genetics & Development·Matthew J Young, William C Copeland
Nov 18, 2008·Biochimica Et Biophysica Acta·Sherine S L Chan, William C Copeland

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