Skip Navigation


Human Molecular Genetics Advance Access originally published online on November 6, 2006
Human Molecular Genetics 2006 15(23):3473-3483; doi:10.1093/hmg/ddl424
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
15/23/3473    most recent
ddl424v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (15)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chan, S. S.L.
Right arrow Articles by Copeland, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chan, S. S.L.
Right arrow Articles by Copeland, W. C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press.

Modulation of the W748S mutation in DNA polymerase {gamma} by the E1143G polymorphismin mitochondrial disorders

Sherine S.L. Chan, Matthew J. Longley and William C. Copeland*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA

* To whom correspondence should be addressed at: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Building 101, Rm E316, Research Triangle Park, NC 27709, USA. Tel: +1 9195414792; Fax: +1 9195417613; Email: copelan1{at}niehs.nih.gov

Received September 19, 2006; Accepted October 23, 2006

DNA polymerase gamma (pol {gamma}) is required for replication and repair of mitochondrial DNA. Over 80 mutations in POLG, the gene encoding the catalytic subunit of pol {gamma}, have been linked with disease. The W748S mutation in POLG is the most common mutation in ataxia-neuropathy spectrum disorders and is generally found in cis with the common E1143G polymorphism. It has been unclear whether E1143G participates in the disease process. We investigated the biochemical consequences of pol {gamma} proteins containing W748S or E1143G, or both. W748S pol {gamma} exhibited low DNA polymerase activity, low processivity and a severe DNA-binding defect. However, interactions between the catalytic and accessory subunits were normal. Despite the benefits derived from binding with the accessory subunit, catalytic activities did not reach wild-type (WT) levels. Also, nucleotide selectivity decreased 2.1-fold compared with WT. Surprisingly, pol {gamma} containing only E1143G was 1.4-fold more active than WT, and this increased polymerase activity could be due to higher thermal stability for E1143G pol {gamma}. The E1143G substitution partially rescued the deleterious effects of the W748S mutation, as DNA binding, catalytic activity and fidelity values were intermediate for W748S-E1143G. However, W748S-E1143G had a notably lower change in enthalpy for protein folding than W748S alone. We suggest that when E1143G is in cis with other pathogenic mutations, it can modulate the effects of these mutations. For W748S-E1143G pol {gamma}, the benefits bestowed by E1143G include increased DNA binding and polymerase activity; however, E1143G was somewhat detrimental to protein stability.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 BMJ Case ReportsHome page
R McFarland, G Hudson, R W Taylor, S H Green, S Hodges, P J McKiernan, P F Chinnery, and V Ramesh
Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase {gamma} (POLG1)
BMJ Case Reports, May 10, 2009; 2009(may10_1): bcr1220081303 - bcr1220081303.
[Abstract] [Full Text]

Home page
 J. Med. Genet.Home page
J D Stewart, S Tennant, H Powell, A Pyle, E L Blakely, L He, G Hudson, M Roberts, D du Plessis, D Gow, et al.
Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children
J. Med. Genet., March 1, 2009; 46(3): 209 - 214.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
N. Ashley, A. O'Rourke, C. Smith, S. Adams, V. Gowda, M. Zeviani, G. K. Brown, C. Fratter, and J. Poulton
Depletion of mitochondrial DNA in fibroblast cultures from patients with POLG1 mutations is a consequence of catalytic mutations
Hum. Mol. Genet., August 15, 2008; 17(16): 2496 - 2506.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
H. Raef, E. Y Baitei, M. Zou, and Y. Shi
Genotype-phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.
Eur. J. Endocrinol., April 1, 2008; 158(4): 577 - 582.
[Abstract] [Full Text] [PDF]

Home page
 Arch. Dis. Child.Home page
R McFarland, G Hudson, R W Taylor, S H Green, S Hodges, P J McKiernan, P F Chinnery, and V Ramesh
Reversible valproate hepatotoxicity due to mutations in mitochondrial DNA polymerase {gamma} (POLG1)
Arch. Dis. Child., February 1, 2008; 93(2): 151 - 153.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
L. Bindoff
Reply
Brain, April 1, 2007; 130(4): E70 - E70.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.