Investigators and Program Directors

Research Interests

Retrotransposons are mobile elements whose movement occurs through an RNA intermediate. Retrotransposons are present in virtually all eukaryotes from yeast to humans, and their movement has been implicated in the formation of inherited disorders and cancers. My laboratory is interested in how the activity of retrotransposons is controlled by the host cell to ensure the stability of the host cell genome.

Long terminal repeat (LTR)-retrotransposons are a class of retroelements that are structurally and functionally related to vertebrate retroviruses. LTR-retrotransposons move by copying their RNA into a linear cDNA using reverse transcriptase (RT) and then inserting the cDNA into the host genome. The movement of LTR-retrotransposons can inactivate or alter the regulation of host genes and can facilitate DNA double-strand break repair, chromosomal rearrangements and pseudogene formation. Although the mutations and rearrangements associated with LTR-retrotransposons are often neutral or deleterious, these elements impart evolutionary plasticity to the genome, thereby contributing to the ability of cells to adapt to new environments. It has been hypothesized that one way in which eukaryotic cells balance the beneficial and deleterious effects of retrotransposons is by mobilizing them specifically in response to genomic insults, when their activity can promote repair or adaptive rearrangements (McClintock, 1984, Science 266:792). This hypothesis predicts that the activity of retrotransposons will be stimulated as a specific response to a DNA lesion. My lab has shown for the first time that an LTR-retrotransposon is activated in response to a specific chromosomal lesion through a highly conserved DNA-damage signaling pathway.

The long-term goal of research in my laboratory is to understand how DNA lesions activate retrotransposons and how this mobilization of elements affects the host genome. Toward this end, we are using the Ty1 retrotransposon in the yeast, Saccharomyces cerevisiae, as a model system. Ty1 is a facile model system to explore the host-retrotransposon relationship because Ty1 elements are one of the most active retrotransposons in eukaryotes, and one of the best studied. Transposition of a single chromosomal Ty1 element under the control of its native promoter can be followed in a sensitive phenotypic assay when the element is marked with a retrotransposition indicator gene. Furthermore, an unparalleled array of genetic, molecular, functional genomics and informatics tools are available for the analysis of yeast.

Most of the ~30 copies of Ty1 in the yeast genome are functional elements, and Ty1 RNA is one of the most abundant mRNA species in yeast cells. Nonetheless, only one copy of Ty1 cDNA is synthesized for every 10,000 Ty1 transcripts, and transposition is rare. Over thirty host factors that inhibit retrotransposition have been identified in my lab and others. Many of these host regulators are previously characterized proteins with conserved roles in genome maintenance, including telomerase. Telomerase is a specialized reverse transcriptase that synthesizes a simple repeat DNA sequence onto the ends of chromosomes, thereby protecting the chromosomes from end-degradation and interchromosomal recombination. We have demonstrated that progressive shortening of telomeres in the absence of telomerase triggers the activation of Ty1 through a DNA-damage signaling pathway. This signaling pathway, which we have named the lesion-induced Ty1 activation pathway, includes the highly conserved DNA damage checkpoint sensors, Rad24, Rad17 and Rad9. The lesion-induced Ty1 activation pathway stimulates the synthesis of Ty1 cDNA. Moreover, our recent data suggests that the elevated levels of reverse transcription may play a role in restructuring the genome in the absence of telomerase to allow cells to continue dividing in the absence of telomerase.

Current work in my laboratory is focused on testing the hypothesis that many of the genome maintenance genes that have been identified as inhibitors of Ty1 transposition prevent the formation of anomalous DNA structures that trigger the lesion-induced Ty1 activation pathway. We are characterizing the lesion-induced Ty1 activation pathway ultimately to identify the effector protein(s) that interacts with a component of the Ty1 retrotransposition complex. Furthermore, we are defining the role of the Ty1 transposition machinery in the formation of alternative telomere structures in telomerase-negative survivors.

Contact Information

E-mail: joan.curcio@wadsworth.org
Phone: (518) 473-6078
Fax: (518) 474-3181