Consequences Of Mitochondrial Dna Damage

Van Houten, Bennett

Abstract

of Work: Faulty DNA repair can lead to increased mutations, formation of cancers, and cell death. The process by which repair proteins find damaged bases within the DNA represents an important type of protein-DNA interaction, which is not well-understood. The UvrA, UvrB,and UvrC proteins work together to identify and remove DNA damage in a process called nucleotide excision repair. One of the most remarkable aspects of NER is that it can remove a wide range of DNA lesions that differ in chemistry and structure. The UvrABC proteins are believed to recognize the damage-induced distortion in the DNA helix rather than the lesion per se. However, detailed studies of the kinetics,thermodynamics and structural aspects of the Uvr proteins have been limited due to the lability and instability of the proteins. To overcome this problem we have recently cloned and overexpressed UvrA, UvrB,and UvrC from the thermophile, Bacillus caldotenax. The proteins maintain their activity at 65oC and are more amenable to structural and biophysical studies. Work is underway to understand the structure and function of these proteins using x-ray crystallography, stopped-flow fluorescence and site-directed mutagenesis.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Environmental Health Sciences (NIEHS)
• Type: Intramural Research (Z01)
• Project #: 1Z01ES061062-03
• Application #: 6508854
• Study Section: (LMG)
• Support Year: 3
• Fiscal Year: 2001

Institution

• Name: U.S. National Inst of Environ Hlth Scis
• Country: United States

Publications

Ma, Wenjian; Panduri, Vijayalakshmi; Sterling, Joan F et al. (2009) The transition of closely opposed lesions to double-strand breaks during long-patch base excision repair is prevented by the coordinated action of DNA polymerase delta and Rad27/Fen1. Mol Cell Biol 29:1212-21

Wielgus, Albert R; Chignell, Colin F; Miller, David S et al. (2007) Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochem Photobiol 83:706-13

Meyer, Joel N; Boyd, Windy A; Azzam, Gregory A et al. (2007) Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans. Genome Biol 8:R70

Santos, Janine Hertzog; Meyer, Joel N; Van Houten, Bennett (2006) Mitochondrial localization of telomerase as a determinant for hydrogen peroxide-induced mitochondrial DNA damage and apoptosis. Hum Mol Genet 15:1757-68

Santos, Janine H; Meyer, Joel N; Mandavilli, Bhaskar S et al. (2006) Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells. Methods Mol Biol 314:183-99

Stuart, Gregory R; Santos, Janine H; Strand, Micheline K et al. (2006) Mitochondrial and nuclear DNA defects in Saccharomyces cerevisiae with mutations in DNA polymerase gamma associated with progressive external ophthalmoplegia. Hum Mol Genet 15:363-74

Van Houten, Bennett; Woshner, Victoria; Santos, Janine H (2006) Role of mitochondrial DNA in toxic responses to oxidative stress. DNA Repair (Amst) 5:145-52

Fariss, Marc W; Chan, Catherine B; Patel, Manisha et al. (2005) Role of mitochondria in toxic oxidative stress. Mol Interv 5:94-111

Mandavilli, Bhaskar S; Boldogh, Istvan; Van Houten, Bennett (2005) 3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. Brain Res Mol Brain Res 133:215-23

Santos, Janine Hertzog; Meyer, Joel N; Skorvaga, Milan et al. (2004) Mitochondrial hTERT exacerbates free-radical-mediated mtDNA damage. Aging Cell 3:399-411