Our Science – Strathern Website

Jeffrey N. Strathern, Ph.D.

Gene Regulation and Chromosome Biology Laboratory Head, Genome Recombination and Regulation Section Laboratory Chief Bldg. 539, Room 152E NCI-Frederick Frederick, MD 21702-1201 Phone:   301-846-1274 Fax:   301-846-6911 E-Mail:   strather@mail.ncifcrf.gov

Biography

Dr. Strathern obtained his Ph.D. from the Molecular Biology Institute at the University of Oregon in 1977, then moved to Cold Spring Harbor Laboratory where he became a senior staff member with the Yeast Genetics Laboratory. In 1984, he joined the ABL-Basic Research Program at the NCI's Frederick Cancer Research Development Center (now NCI-Frederick). His research remains centered on aspects of gene regulation and genetic recombination as revealed by studies in yeast. In 1999, Dr. Strathern joined the Division of Basic Sciences, NCI. In March 2001, the Division of Basic Sciences merged with the Division of Clinical Sciences to form the NCI Center for Cancer Research.

Research

Two general areas of research are pursued in our section: mechanisms of genetic recombination and mechanisms of gene regulation. These areas come together in the control of mating type in yeast, where cell type is changed by a programmed genetic rearrangement that allows expression of alternative genes encoding trans-acting regulatory proteins. The programmed recombination event is initiated by a site-specific DNA cleavage. Our studies of this process led us into the area of genetic recombination in general and double-strand-break repair in particular. Currently, we are screening for strains defective in recombination to define additional functions involved in this process. We expect that such genes could add to the list of recombination and DNA damage repair defects known to be related to neoplastic disease. We recently demonstrated that the DNA synthesis associated with genetic recombination has substantially lower fidelity than that found in general cell duplication. Our recent results suggest at least two different DNA polymerases have roles in this elevated mutation rate: Base substitutions reverting a non-sense allele are dependent on the translesion polymerase, Pol zeta, encoded by REV3, whereas reversion of frameshift alleles is REV3 independent. We continue to investigate the mechanism of double-strand-break repair and the proteins involved in controlling the fidelity of DNA synthesis during this process. We are currently determining the rate-limiting steps in meiotic recombination between ectopic sites.

We demonstrated that reverse transcription of cellular mRNAs can generate substrates for recombination, resulting in processed pseudogenes and RNA-mediated gene conversion. We continue to explore the role of reverse transcripts in genome evolution. In a collaboration with David Garfinkel, we developed an in vivo assay for HIV-1 reverse transcriptase (RT), based on hybrid Ty1/HIV-1 elements and a homologous recombination assay. This assay is sensitive to some known nonnucleoside inhibitors of HIV-1 RT. In collaboration with Christopher Michejda, we have also identified several new drugs that inhibit HIV-1 RT. This year, we initiated an analysis of the fidelity of retrotransposition using tools similar to those used in our studies of the fidelity of recombination. This topic provides us with an opportunity to investigate not only the features of RT that govern its fidelity, but also an opportunity to investigate the properties that govern the fidelity of RNA polymerase.

Our interests in gene regulation are currently centered on the mechanism of gene silencing. This mechanism was first discovered as the means of inhibiting the transcription of donor loci used in the recombination event associated with mating-type switching in yeast. The source copies of the genes activated in this process are kept silent by the SIR genes (silent information regulators) and several other genes. A demonstrated role of histones, and an altered accessibility of the DNA in the silenced region, implicates chromatin modification within a defined domain as the means by which silencing occurs. The SIR2 gene has also been shown to have a role in silencing near the telomeres and in controlling recombination in the rDNA repeats. We showed that yeast has five genes closely related to SIR2 and that SIR2 homologs can be found in organisms ranging from prokaryotes to humans. We are continuing to define the roles of this gene family in genome regulation.

Our collaborators are Stephen Hughes and Christopher Michejda, NIH.

This page was last updated on 6/12/2008.