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Molecular and Cellular Biology, February 2009, p. 794-807, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01357-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress{triangledown}

Lyra M. Griffiths,1,2 Dan Swartzlander,1,2 Kellen L. Meadows,1,{dagger} Keith D. Wilkinson,1,3 Anita H. Corbett,1,3 and Paul W. Doetsch1,3,4,5*

Department of Biochemistry,1 Graduate Program in Genetics and Molecular Biology,2 Emory Winship Cancer Institute,3 Department of Radiation Oncology,4 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia5

Received 26 August 2008/ Returned for modification 22 September 2008/ Accepted 15 November 2008

DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

* Corresponding author. Mailing address: Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd., Atlanta, GA 30322. Phone: (404) 727-0409. Fax: (404) 727-2618. E-mail: medpwd{at}emory.edu

{triangledown} Published ahead of print on 24 November 2008.

{dagger} Present address: Duke Clinical Research Institute, Durham, NC 27705.

Molecular and Cellular Biology, February 2009, p. 794-807, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01357-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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