Thomas Petes
Minnie Geller Distinguished Professor of Research in Genetics, in the School of Medicine
Overview
My lab is active in three somewhat related research areas: 1) the mechanism of mitotic recombination, 2) the genetic regulation of genome stability, and 3) genetic instability associated with interstitial telomeric sequences. Almost all of our studies are done using the yeast Saccharomyces cerevisiae.
Mechanism of mitotic recombination
Mitotic recombination, an important mechanism for the repair of DNA damage, is less well characterized than meiotic recombination. One difficulty is that mitotic recombination events are 104-fold less frequent than meiotic recombination events. We developed a greatly improved system for identifying and mapping mitotic crossovers at 1-kb resolution throughout the genome. This system uses DNA microarrays to detect loss of heterozygosity (LOH) resulting from mitotic crossovers. We identified motifs associated with high levels of spontaneous mitotic recombination. In particular, we demonstrated that a “hotspot” for mitotic recombination was generated by a pair of inverted retrotransposons. We also used this system to make the first genome-wide map of UV-induced recombination events. Finally, and most importantly, we demonstrated that most spontaneous mitotic recombination events reflect the repair of two sister-chromatids broken at the same position. This result argues that the DNA lesions that initiate mitotic recombination are a consequence of chromosome breakage in unreplicated DNA, contrary to the common belief that most recombinogenic lesions reflect broken replication forks. We are currently analyzing recombination events that occur in the absence of DNA mismatch repair.
Genetic regulation of genome stability
In wild-type cells, the frequency of genomic alterations of any type (point mutations, deletions, insertions, and chromosome rearrangements) is very low. We are interested in the genes that regulate genome stability. One rationale for this interest is that the cells of most solid tumors have very high levels of chromosome rearrangements (deletions, duplications, and translocations) as well as high levels of aneuploidy. To understand this type of instability, we are examining the chromosome instability associated with various genome-destabilizing conditions in yeast. We are currently concentrating on mutations that affect DNA replication. We have mapped chromosome rearrangements in yeast strains with low levels of DNA polymerase alpha. This mapping indicated that DNA breaks occur in regions of the genome in which replication forks are slowed or stalled. This pattern of recombination events is quite different from that observed in cells with normal replication. In collaboration with Sue Jinks-Robertson’s lab, we have also characterized chromosome alterations in strains with mutations in Topoisomerase I and cells treated with Topoisomerase I inhibitors. Our analysis is currently being extended into strains with mutations affecting Topoisomerase II, and mutations in DNA damage repair checkpoint genes. Our preliminary study shows that loss of Topoisomerase II results in an interesting pattern of chromosome non-disjunction in which chromosomes segregate in a manner similar to the first division of meiosis.
Genetic regulation of genome stability
Although telomeric sequences are usually located at the ends of the chromosome, mammalian chromosomes also have interstitial telomeric repeats (ITSs), and these ITSs are often sites of chromosome rearrangements in tumor cells. In collaboration with Sergei Mirkin’s lab, we developed methods of detecting ITS-induced genome instability in yeast. We are currently examining the effects of mutations in recombination (RAD52, RAD51, MUS81, RAD50, MRE11, LIG4, RAD59), DNA repair (RAD1, MSH2), DNA replication (REV3), and telomere length maintenance (TEL1, RIF1) pathways on the rates and types of ITS-induced events. The goal of this project is to identify the proteins required to initiate DNA lesions at ITSs and the proteins required to catalyze the ITS-associated rearrangements.
Positions
Minnie Geller Distinguished Professor of Research in Genetics, in the School of Medicine in the School of Medicine
2006 School of Medicine
Professor of Molecular Genetics and Microbiology in the School of Medicine
2006 School of Medicine
Professor of Cell Biology in the School of Medicine
2022 School of Medicine
Member of the Duke Cancer Institute in the School of Medicine
2004 School of Medicine
Education
Ph.D. 1973
1973 University of Washington
Publications, Grants & Awards
- Grants (16)
- Awards (4)
- Academics Articles (200)
- Conference Pages (2)
National Institutes of Health
National Institutes of Health
Army Research Office
National Institutes of Health
National Institutes of Health
Army Research Office
National Institutes of Health
National Institutes of Health
Army Research Office
National Institutes of Health
National Institutes of Health
National Cancer Institute
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
Genetics Society of America
American Association for the Advancement of Science
American Academy of Arts and Sciences
National Academy of Science
Nucleic Acids Res
Nucleic Acids Res
Proc Natl Acad Sci U S A
Curr Opin Genet Dev
Nucleic Acids Res
Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
Molecular and Cellular Biology
Nucleic Acids Res
Microbial Cell (Graz, Austria)
Proc Natl Acad Sci U S A
Genetics
Mbio
Proc Natl Acad Sci U S A
G3 (Bethesda, Md.)
Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
Genetics
Dna Repair (Amst)
Proc Natl Acad Sci U S A
Genetics
Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
Genome Res
Plos Genet
The Embo Journal
Molecular and Cellular Biology
Molecular and Cellular Biology
Proc Natl Acad Sci U S A
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
The Journal of Biological Chemistry
Molecular Cell
Proceedings of the National Academy of Sciences of the United States of America
Genetics
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Nature Reviews. Genetics
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Genetics
Molecular and Cellular Biology
Genetics
Mutation Research
Molecular and Cellular Biology
Nucleic Acids Research
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Advances in Genetics
Yeast (Chichester, England)
Molecular and Cellular Biology
Current Genetics
Human Molecular Genetics
American Journal of Human Genetics
Proceedings of the National Academy of Sciences of the United States of America
Molecular and Cellular Biology
Molecular and Cellular Biology
Methods in Enzymology
Molecular and Cellular Biology
Molecular and Cellular Biology
Molecular and Cellular Biology
Current Genetics
Proceedings of the National Academy of Sciences of the United States of America
Genetics
Genetics
Proceedings of the National Academy of Sciences of the United States of America
Genetics
Molecular and Cellular Biology
Molecular and Cellular Biology
Genetics
Science (New York, N.Y.)
Molecular and Cellular Biology
Genetics
Molecular and Cellular Biology
Annual Review of Genetics
Nucleic Acids Research
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Proceedings of the National Academy of Sciences of the United States of America
Journal of Molecular Biology
Nucleic Acids Research
Molecular and Cellular Biology
Molecular and Cellular Biology
American Journal of Human Genetics
Journal of Molecular Evolution
American Journal of Human Genetics
Genetics
Genetics
Current Genetics
Journal of Bacteriology
Annual Review of Biochemistry
Molecular & General Genetics : Mgg
Journal of Bacteriology
Proceedings of the National Academy of Sciences of the United States of America
Journal of Bacteriology
Journal of Bacteriology
Cold Spring Harbor Symposia on Quantitative Biology
Proceedings of the National Academy of Sciences of the United States of America
Experimental Cell Research
Cold Spring Harbor Symposia on Quantitative Biology
Biochemical and Biophysical Research Communications
Proceedings of the National Academy of Sciences of the United States of America
Symposia on Quantitative Biology
Proceedings of the National Academy of Sciences of the United States of America
STRUCTURE, MOTION, INTERACTION AND EXPRESSION OF BIOLOGICAL MACROMOLECULES, VOL 2
GENOME REARRANGEMENT AND STABILITY
Offices & Contact
Durham, NC
27710 Duke Box 3054
Durham, NC
27710