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Research Fellow Reviews Role of Protein Mutations in Mitochondria

By Senyene Hunter
July 2008

Among her accomplishments, NIEHS Research Fellow Sherine Chan was a co-author on a study linking defects in mtDNA replication to cardiac dysfunction that was selected as an Intramural Paper of the Month in June 2007.
Among her accomplishments, NIEHS Research Fellow Sherine Chan was a co-author on a study (http://www.ncbi.nlm.nih.gov/pubmed/17310215?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum) linking defects in mtDNA replication to cardiac dysfunction that was selected as an Intramural Paper of the Month in June 2007. (Photo courtesy of Steve McCaw)

On June 11 in Rall Building Conference Room D350, Sherine Chan, Ph.D., presented her research to the NIEHS Laboratory of Molecular Genetics (LMG) investigators as a part of the LMG Wednesday Seminar Series. Chan, who is a Research Fellow in the Mitochondrial DNA Replication Group, spoke on "Proteins at the Mitochondrial DNA Replication Fork."

Chan's presentation highlighted the importance of studying mitochondrial DNA (mtDNA) replication in the context of learning more about mitochondrial diseases. "Mutations in genes that encode mtDNA replication proteins cause mitochondrial disease." explained Chan. "Mitochondrial diseases are associated with defects in the mitochondrial genome or are characterized by any disease that has a large mitochondrial component."

Chan stressed that as many as 1 in 2000 to 1 in 5000 people - both children and adults - are devastated by mitochondrial myopathies, for which there are currently no cures. Mitochondria are responsible for generating most of the requisite cellular energy. Mitochondrial diseases are characterized by deficits in energy production due to the disruption of oxidative phosphorylation. They include such conditions as progressive external ophthalmoplegia, sensory and ataxic neuropathy, Alpers syndrome, hepatocerebral syndromes and male infertility.

Chan opened her talk by describing work that she has done over the past year in the Mitochondrial DNA Replication Group(http://www.niehs.nih.gov/research/atniehs/labs/lmg/mdnar/index.cfm) headed by Principal Investigator William Copeland, Ph.D. Her presentation focused on three proteins that, along with others, comprise the mitochondrial DNA replication machinery: the catalytic subunit of DNA polymerase gamma (pol ?), its accessory subunit p55 and the mtDNA helicase PEO1. Initial studies by Chan and her colleagues resulted in the biochemical characterization of these proteins. This work greatly advanced the field in the understanding of DNA replication proteins and their involvement in mitochondrial disease.

More than 150 mutations have been found in pol ? that result in mitochondrial disease. The group maintains a database of all known pol ? mutations along with their associated clinical phenotypes(http://tools.niehs.nih.gov/polg/). The genes encoding p55 and PEO1 also have mutations that result in disease states. Chan and other members of the group have expressed and biochemically characterized several of these variant proteins to determine how the mutations affect protein stability and/or function. The aim of the group is to determine the link between the observed protein mutations and the resulting clinical phenotypes.

(Senyene Hunter, Ph.D., is a postdoctoral fellow in the NIEHS DNA Repair and Mitochondrial Damage Group.)



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