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Genome-Wide Analysis of Signal Transducers and Regulators of Mitochondrial Dysfunction in Saccharomyces cerevisiae
aDepartment of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA bDepartment of Life Sciences and Chemistry, Roskilde University, 4000 Roskilde, Denmark
Address for correspondence: Keshav K. Singh, Ph.D., Department of Cancer Genetics, Cell and Virus Building, Room 247, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. Voice: 716-845-8017; fax: 716-845-1047. keshav.singh{at}roswellpark.org Ann. N.Y. Acad. Sci. 1011: 284-298 (2004).
Mitochondrial dysfunction is a hallmark of cancer cells. However, genetic response to mitochondrial dysfunction during carcinogenesis is unknown. To elucidate genetic response to mitochondrial dysfunction we used Saccharomyces cerevisiae as a model system. We analyzed genome-wide expression of nuclear genes involved in signal transduction and transcriptional regulation in a wild-type yeast and a yeast strain lacking the mitochondrial genome (rho0). Our analysis revealed that the gene encoding cAMP-dependent protein kinase subunit 3 (PKA3) was upregulated. However, the gene encoding cAMP-dependent protein kinase subunit 2 (PKA2) and the VTC1, PTK2, TFS1, CMK1, and CMK2 genes, involved in signal transduction, were downregulated. Among the known transcriptional factors, OPI1, MIG2, INO2, and ROX1 belonged to the upregulated genes, whereas MSN4, MBR1, ZMS1, ZAP1, TFC3, GAT1, ADR1, CAT8, and YAP4 including RFA1 were downregulated. RFA1 regulates DNA repair genes at the transcriptional level. RFA is also involved directly in DNA recombination, DNA replication, and DNA base excision repair. Downregulation of RFA1 in rho0 cells is consistent with our finding that mitochondrial dysfunction leads to instability of the nuclear genome. Together, our data suggest that gene(s) involved in mitochondria-to-nucleus communication play a role in mutagenesis and may be implicated in carcinogenesis.
Key Words: mitochondria • mutagenesis • repair • yeast • cancer This article has been cited by other articles:
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