Cellular Aging

Our laboratory is interested in the cellularbasis for aging. There are a number of mechanisms that operateat the cellular level to contribute to the aging process, including,but not limited to: (1) genomic instability; (2) reactive oxygenspecies (ROS) damage; and (3) impaired DNA repair pathways. Genomicinstability includes loss and rearrangement of genetic informationin either dividing or non-dividing cells. For example, shorteningof telomeres (loss of telomeric repeat sequences) at chromosomaltermini in dividing cells leads to replicative senescence (failureto divide). We are investigating genomic instability in the buddingyeast Saccharomyces cerevisiae. We use yeast as an experimentalsystem because of the ease of using various approaches in biochemistry,cell biology, genetics, and molecular biology. Yeast divide asymmetrically.A larger "mother" cell gives rise to a smaller "daughter"cell through a budding process (rather than cell fission). Mothercells typically divide less than 50 times, and hence typicallygive rise to less than 50 daughters. A number of single gene mutationshave been identified in yeast that affect the "replicativelifespan" of mother cells (i.e., the number of daughtersthat can be produced). This indicates that the lifespan of yeastmother cells is regulated. So far, certain genes in yeast thathave been shown to regulate lifespan (such as SIR2) alsoregulate lifespan in other organisms, such as the nematode C.elegans. Thus, our goal is to pursue an understanding of mechanismsthat regulate replicative lifespan in yeast cells and extend ourstudies to other cells types in order to better understand generalmechanisms that influence aging at the cellular level.

RNA Processing

Our laboratory is also interested in ribosomalRNA processing and modification, nucleolar function, and ribosomebiogenesis. The nucleolus is a well-known, ultrastructurally distinctregion within the nucleus, and is dedicated to the synthesis ofthe large and small ribosome subunits. We have identified, molecularlycloned, and studied novel nucleolar proteins in the yeast S.cerevisiae. Our studies have concentrated on exploring theroles of nucleolar proteins in rRNA processing and modification,and ribosome assembly. Over the long term, we wish to understandmechanisms by which nucleolar activity is regulated and coordinatedwith cell growth control, including the aging process.

1. Hong, B., K. Wu, J. Scott Brockenbrough, P. Wu, and J. P. Aris. 2001. Temperature sensitive nop2 alleles defective in synthesis of 25S rRNA and large ribosomal subunits in Saccharomyces cerevisiae. Nucleic Acids Res. 29:2927-37.
2. Wu, K., P. Wu, and J. P. Aris. 2001. Nucleolar protein Nop12p participates in synthesis of 25S rRNA in Saccharomyces cerevisiae. Nucleic Acids Res. 29:2938-49.
3. Nelson, S. A, J. P. Aris, B. K. R. Patel, and W. J. LaRochelle. 2000. Multiple growth factor transcriptional activation of SAN5, a murine early response gene that complements a lethal defect in yeast ribosome biogenesis. J. Biol. Chem. 275:13835Ð13841.
4. Wu, K., J. H. Dawe, J. P. Aris. 2000. Expression and subcellular localization of a membrane protein related to Hsp30p in Saccharomyces cerevisiae. Biochim. Biophys. Acta 1463:477-482.
5. Oakes, M., J. P. Aris, J. S. Brockenbrough, H. Wai, L. Vu, and M. Nomura. 1998. Mutational analysis of the structure and localization of the nucleolus in the yeast Saccharomyces cerevisiae. J. Cell Biol. 143:23-34.
6. Wu, P., J. S. Brockenbrough, M. R. Paddy, and J. P. Aris. 1998. NCL1, a novel gene for a non-essential nuclear protein in Saccharomyces cerevisiae. Gene 220:109-117.
7. Wu, P., J. S. Brockenbrough, A. Metcalfe, S. Chen, and J. P. Aris. 1998. Nop5p is a small nucleolar ribonucleoprotein component required for pre-18S rRNA processing in yeast. J. Biol. Chem. 273:16453-63.
8. Dove, J. E., J. S. Brockenbrough, and J. P. Aris. 1998. Isolation of nuclei and nucleoli from the yeast Saccharomyces cerevisiae. (M. Berrios, ed.) Methods Cell Biol. 53:33-46.
9. Chen, S., J. E. Dove, J. S. Brockenbrough, and J. P. Aris. 1997. Homocitrate synthase is located in the nucleus in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 272:10839-10846.
10. B. Hong, J. S. Brockenbrough, P. Wu, and J. P. Aris. 1997. Nop2p is required for pre-rRNA processing and 60S ribosome subunit synthesis in yeast. Mol. Cell. Biol. 17:378-388.