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Molecular and Cellular Biology, March 2001, p. 1647-1655, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1647-1655.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pir1p Mediates Translocation of the Yeast Apn1p Endonuclease into the Mitochondria To Maintain Genomic Stability

Ratsavarinh Vongsamphanh, Pierre-Karl Fortier, and Dindial Ramotar*

Guy-Bernier Research Centre, University of Montreal, Montreal, Quebec, Canada H1T 2M4

Received 1 September 2000/Returned for modification 21 November 2000/Accepted 30 November 2000

The mitochondrial genome is continuously subject to attack by reactive oxygen species generated through aerobic metabolism. This leads to the formation of a variety of highly genotoxic DNA lesions, including abasic sites. Yeast Apn1p is localized to the nucleus, where it functions to cleave abasic sites, and apn1 Delta  mutants are hypersensitive to agents such as methyl methanesulfonate (MMS) that induce abasic sites. Here we demonstrate for the first time that yeast Apn1p is also localized to the mitochondria. We found that Pir1p, initially isolated as a cell wall constituent of unknown function, interacts with the C-terminal end of Apn1p, which bears a bipartite nuclear localization signal. Further analysis revealed that Pir1p is required to cause Apn1p mitochondrial localization, presumably by competing with the nuclear transport machinery. pir1Delta mutants displayed a striking (~3-fold) increase of Apn1p in the nucleus, which coincided with drastically reduced levels in the mitochondria. To explore the functional consequences of the Apn1p-Pir1p interaction, we measured the rate of mitochondrial mutations in the wild type and pir1Delta and apn1Delta mutants. pir1Delta and apn1Delta mutants exposed to MMS exhibited 3.6- and 5.8-fold increases, respectively, in the rate of mitochondrial mutations, underscoring the importance of Apn1p in repair of the mitochondrial genome. We conclude that Pir1p interacts with Apn1p, at the level of either the cytoplasm or nucleus, and facilitates Apn1p transport into the mitochondria to repair damaged DNA.

* Corresponding author. Mailing address: University of Montreal, Guy-Bernier Research Centre, 5415 de l'Assomption, Montreal, Quebec, Canada H1T 2M4. Phone: (514) 252-3400, ext. 4684. Fax: (514) 252-3430. E-mail: dramotar{at}hmr.qc.ca.

Molecular and Cellular Biology, March 2001, p. 1647-1655, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1647-1655.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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