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LABORATORY OF GENE REGULATION AND DEVELOPMENT

Alan G. Hinnebusch, PhD, Chief

Five of the eight groups in the Laboratory of Gene Regulation and Development (LGRD) study transcriptional and translational control of gene regulation, chromosome condensation and segregation, and the transposition of retroelements in budding or fission yeast

The Section on Nutrient Control of Gene Expression, headed by Alan Hinnebusch, studies the transcriptional and translational control of amino acid biosynthetic genes in response to nutrient availability. Recently, the section implicated translation initiation factor 3 (eIF3) in scanning and AUG recognition and showed that overexpression of the YIH1 protein inhibits the eIF2alpha protein kinase GCN2. The section also showed that the transcriptional activator GCN4 recruits a multiplicity of co-factors to its target promoters to simulate assembly of the pre-initiation complex.

The Section on Protein Biosynthesis, headed by Thomas Dever, is characterizing the structure and function of several translation initiation factors and the molecular principles of kinase-substrate recognition. His section recently determined that residues remote from the phosphorylation site contribute to substrate recognition by the eIF2alpha kinases and that the Switch 1 and 2 elements in the GTPase eIF5B functionally cooperate for the GTP binding and hydrolysis activities that govern the ribosome-binding affinity of this factor.

Rohinton Kamakaka’s group, the Unit on Chromatin and Transcription, studies chromatin dynamics in yeast and has shown that the histone variant Htz1 facilitates DNA replication and normal cell cycle progression. Studies on silenced chromatin domains led the unit to identify elements that block silencing and to show that multiple chromatin remodeling proteins function by distinct mechanisms to restrict the spread of silenced domains.

The Unit on Chromosome Structure and Function, headed by Alexander Strunnikov, is studying SMC protein complexes controlling the fidelity of mitotic chromosome segregation, focusing primarily on the condensin complex and its role in mitotic chromosome condensation. Recently, the unit discovered a novel pathway controlling the targeting of condensin to specialized chromatin regions via activation of Cdc14 phosphatase. The unit’s studies also elucidated the molecular basis for the role of sumoation in chromosome transmission in positive regulation of topoisomerase II by sumoation.

Led by Henry Levin, the Section on Eukaryotic Transposable Elements analyzes an LTR-retrotransposon in S. pombe as a model for retroviruses; the section aims to identify the molecular mechanisms of reverse transcription, the import of particles into the nucleus, and the site specificity of cDNA integration. Recently, the section demonstrated preferential insertion of Tf1 into the promoters of Pol II genes and obtained evidence that such specificity is mediated by interactions between integrase and histone proteins. Biochemical studies with recombinant integrase have revealed that the protein possesses strong integration activity and that the C-terminal domain functions as a negative regulator of integration.

Chi-Hon Lee’s group, the Unit on Neuronal Connectivity, investigates the mechanism by which cadherin-based adhesion specifies the synaptic connections in the Drosophila visual system. Recently, his group showed that the neuronal cadherin (Ncad) locus contains three pairs of alternatively spliced exons and produces transcripts encoding all eight possible isoforms. Using a cell aggregation assay, the group found that all eight isoforms mediate homo- and heterophilic interactions and that the homophilic interactions exhibit different affinities and calcium sensitivities. Thus, Lee proposed that Ncad isoforms mediate graded and calcium-regulated interactions during development.

The anuran Xenopus laevis serves as a model system for two groups. Under Yun-Bo Shi, the Section on Molecular Morphogenesis studies the gene-regulatory mechanisms involving thyroid hormone receptor (TR) that establish the developmental program of metamorphosis. The section has demonstrated in vivo that gene activation by TR, involving co-factor recruitment and histone acetylation, is necessary and sufficient for most, if not all, metamorphic events. The section has also revealed a critical role for the TR-regulated matrix metalloproteinase stromelysin-3 in remodeling of the extracellular matrix during metamorphosis.

Mary Dasso leads the Section on Cell Cycle Regulation, which studies the Ran GTPase and the SUMO family of ubiquitin-like proteins in Xenopus. During the past year, the section has analyzed the function of the GTPase activating protein for Ran (RanGAP1) and its binding partner RanBP2 on the kinetochores of mitotic chromosomes. The researchers have shown that loss of this complex from kinetochores leads to defects in mitotic spindle function and progression through mitosis. They have also documented that different SUMO paralogues are used with a high level of specificity in vertebrate cells. They are currently investigating the molecular mechanisms underlying both of these phenomena.