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Common Mitochondrial DNA Mutations Generated through DNA-Mediated Charge Transport

Merino, Edward J. and Davis, Molly L. and Barton, Jacqueline K. (2009) Common Mitochondrial DNA Mutations Generated through DNA-Mediated Charge Transport. Biochemistry, 48 (4). pp. 660-666. ISSN 0006-2960. PMCID PMC2668510. https://resolver.caltech.edu/CaltechAUTHORS:20090918-080256727

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Abstract

Mutation sites that arise in human mitochondrial DNA as a result of oxidation by a rhodium photooxidant have been identified. HeLa cells were incubated with [Rh(phi)2bpy]Cl3 (phi is 9,10-phenanthrenequinone diimine), an intercalating photooxidant, to allow the complex to enter the cell and bind mitochondrial DNA. Photoexcitation of DNA-bound [Rh(phi)2bpy]3+ can promote the oxidation of guanine from a distance through DNA-mediated charge transport. After two rounds of photolysis and growth of cells incubated with the rhodium complex, DNA mutations in a portion of the mitochondrial genome were assessed via manual sequencing. The mutational pattern is consistent with dG to dT transversions in the repetitive guanine tracts. Significantly, the mutational pattern found overlaps oxidative damage hot spots seen previously. These mutations are found within conserved sequence block II, a critical regulatory element involved in DNA replication, and these have been identified as sites of low oxidation potential to which oxidative damage is funneled. On the basis of this mutational analysis and its correspondence to sites of long-range oxidative damage, we infer a critical role for DNA charge transport in generating these mutations and, thus, in regulating mitochondrial DNA replication under oxidative stress.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bi801570jDOIArticle
http://pubs.acs.org/doi/full/10.1021/bi801570jPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668510/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2009 American Chemical Society. Received August 20, 2008; Revised Manuscript Received October 31, 2008. We are grateful to the NIH (GM49216) for their financial support of this research, including a minority postdoctoral fellowship to E.J.M.
Funders:
Funding AgencyGrant Number
NIHGM49216
NIH Postdoctoral FellowshipUNSPECIFIED
Issue or Number:4
PubMed Central ID:PMC2668510
Record Number:CaltechAUTHORS:20090918-080256727
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090918-080256727
Official Citation:Common Mitochondrial DNA Mutations Generated through DNA-Mediated Charge Transport Edward J. Merino, Molly L. Davis, Jacqueline K. Barton Biochemistry 2009 48 (4), 660-666
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:15942
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:18 Sep 2009 22:35
Last Modified:03 Oct 2019 01:05

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