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Thomas Douglas Petes

Minnie Geller Distinguished Professor of Research in Genetics, in the School of Medicine
Molecular Genetics and Microbiology
Duke Box 3054, Durham, NC 27710
366 CARL Bldg., Box 3054 Med. Ctr., Durham, NC 27710

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.

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.

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.

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.

Current Appointments & Affiliations


Minnie Geller Distinguished Professor of Research in Genetics, in the School of Medicine · 2006 - Present Molecular Genetics and Microbiology, Basic Science Departments
Professor of Molecular Genetics and Microbiology · 2006 - Present Molecular Genetics and Microbiology, Basic Science Departments
Professor of Cell Biology · 2022 - Present Cell Biology, Basic Science Departments
Member of the Duke Cancer Institute · 2004 - Present Duke Cancer Institute, Institutes and Centers

In the News


Published May 7, 2014
Faulty DNA-copying may lead to cancer
Published May 5, 2014
Where DNA's Copy Machine Pauses, Cancer Could Be Next

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Recent Publications


A tale of two serines: the effects of histone H2A mutations S122A and S129A on chromosome nondisjunction in Saccharomyces cerevisiae.

Journal Article Genetics · January 8, 2025 Near the C-terminus of histone H2A in the yeast Saccharomyces cerevisiae, there are 2 serines (S122 and S129) that are targets of phosphorylation. The phosphorylation of serine 129 in response to DNA damage is dependent on the Tel1 and Mec1 kinases. In Sch ... Full text Link to item Cite

Dicentric chromosomes are resolved through breakage and repair at their centromeres.

Journal Article Chromosoma · April 2024 Chromosomes with two centromeres provide a unique opportunity to study chromosome breakage and DNA repair using completely endogenous cellular machinery. Using a conditional transcriptional promoter to control the second centromere, we are able to activate ... Full text Link to item Cite

Splitting the yeast centromere by recombination.

Journal Article Nucleic Acids Res · January 25, 2024 Although fusions between the centromeres of different human chromosomes have been observed cytologically in cancer cells, since the centromeres are long arrays of satellite sequences, the details of these fusions have been difficult to investigate. We deve ... Full text Link to item Cite
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Recent Grants


Tri-Institutional Molecular Mycology and Pathogenesis Training Program

Inst. Training Prgm or CMEMentor · Awarded by National Institutes of Health · 2024 - 2029

Genetic regulation of genome stability in yeast

ResearchPrincipal Investigator · Awarded by National Institute of General Medical Sciences · 2016 - 2026

Regulation of genome stability in the yeast Saccharomyces cerevisiae by temperature

ResearchPrincipal Investigator · Awarded by Army Research Office · 2022 - 2025

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Education, Training & Certifications


University of Washington · 1973 Ph.D.