Research Interests
Most malignant cells have elevated levels of genome instability. The mutated genes responsible for this instability have been identified in only a few types of tumors. We are interested in analyzing the genetic regulation of genome instability in the yeast Saccharomyces cerevisiae as a model for understanding the genetic instability associated with human cancers.
In a study that we performed in 1993, we showed that mutations in DNA mismatch repair genes led to very high rates of alterations in the lengths of simple repetitive DNA sequences (microsatellites) in yeast. Since a high rate of microsatellite instability had been observed in familial colorectal cancers, our results suggested that this type of cancer might reflect a defect in DNA mismatch repair; this suggestion was subsequently proven correct in the labs of Vogelstein, Kolodner, Fisher, and Liskay. We are currently extending our analysis of DNA mismatch repair to a different organism, the nematode C. elegans (as described below).
Our second area of research concerns telomere length regulation. In 1995, we identified the yeast TEL1 gene, a gene required to maintain wild-type telomere length. We showed that this gene was closely related to ATM, the gene mutated in patients with the cancer-prone ataxia telangiectasia syndrome. We have recently shown that yeast strains with mutations in TEL1 and the related gene MEC1 (homologous to the human ATR gene) have very high levels of chromosome rearrangements and deletions. This phenotype resembles the genetic instability observed in CIN- cancers (cancers with karyotypic abnormalities). As described below, we are developing novel methods to determine the mechanisms responsible for this instability.

Recent Accomplishments and Honors
Our research accomplishments have been in three different areas. First, in collaboration with Joseph Culotti, we identified a mutant of C. elegans that had a defective DNA mismatch repair system. We showed that worms with this mutation develop normally, but have very elevated levels of microsatellite instability. Interestingly, we found that serially-passaged worm lines with this mutation became extinct. Thus, the elevated mutation rate associated with a defect in DNA mismatch repair is too high to be tolerated, in the long-term, in a population.
We analyzed in detail the genetic instability found in tel1 mec1 yeast strains. We showed that these strains have very high rates of mutation, chromosome loss, and mitotic recombination. We developed a PCR-based assay that revealed that tel1 mec1 strains had high rates of telomere-telomere fusions. These results suggest that the telomere defect associated with this mutant genotype results in telomere-telomere fusions, generating dicentric chromosomes. Attempts to segregate the dicentric chromosome in mitosis lead to chromosome breaks which, in turn, results in chromosome loss and other types of chromosome rearrangements. Using DNA microarrays, we found that chromosome translocations are very common in tel1 mec1 strains, and that these translocations often have transposable elements at the translocation breakpoints.
We also developed a method of mapping meiotic recombination hotspots (regions of enhanced recombination) and coldspots (regions of reduced recombination) in yeast using DNA microarrays. This method, in principle, can be extended to any eukaryote. We have found that all yeast chromosomes have 25-100 kb regions near the telomeres and centromeres in which recombination is suppressed. We are currently investigating the mechanism of this suppression.
Honors:
Elected to National Academy of Sciences, 1999
Keynote Speaker, FASEB Meeting on Recombination and Genome
Rearrangements, 2001
Vice President, Genetics Society of America, 2001
President, Genetics Society of America, 2002
Kenan Distinguished Professor, 2002-

Training

I have trained 18 graduate students and 20 post-doctoral researchers. Two of my post-doctoral researchers (Jennifer Gerton and Francine Lemoine) have been supported by the training grant.

Publications
Strand M, Prolla TA, Liskay RM, Petes TD. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature. 1993 Sep 16; 365 (6443): 274-8.

Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaeier B, Petes TD. TEL1, a gene involved in regulating telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell. 1995 Sep 8; 83(5): 823-9.

Craven RJ, Greenwell PW, Dominska M, Petes TD. Regulation of genome instability by TEL1 and MEC1, yeast homologoues of the mammalian ATM and ATR genes. Genetics. 2-2 Jun; 161(2): 493-507.

Degtyareva, NP, Greenwell P, Hofmann ER, Hengartner MO, Zhang L, Culotti JG, Petes TD. Caenorhabditis elegans DNA mismatch repair gene msh-2 is required for microsatellite stability and maintenance of genome integrity. Proc. Natl. Acad. Sci. USA 2002 Feb 19; 99(4): 2158-63.

Gerton JL, DeRisi J, Shroff R, Lichten M, Brown PO, Petes TD. Inaugural article: global mapping of meiotic recombination hotspots and coldspots in the yeast Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 2000 Oct 10; 97(25):11383-90.

Mieczkowski, P., Mieczkowska, J., Dominska, M., and Petes, T. Genetic regulation of telomere-telomere fusions in the yeast Saccharomyces cerevisae. Proc. Natl. Acad. Sci. USA 2003 Sept. 16; 100(19):10854-59.

E-mail: tompetes@email.unc.edu
Telephone: (919) 962-1330
FAX: (919) 962-1625
Address: 408 Fordham Hall, CB# 3280 Chapel Hill, NC
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