Alan G. Hinnebusch, PhD, Chief
Four of the seven 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. Another group investigates the molecular basis of connection specificity in the Drosophila visual system; the aneuran Xenopus laevis serves as a model system for the work of the remaining two groups.
The Section on Nutrient Control of Gene Expression, headed by Alan Hinnebusch, studies transcriptional and translational control of amino acid biosynthetic genes by nutrient availability. Recently, the group demonstrated in vivo functions for the translation initiation factor eIF1A in ribosomal scanning and AUG recognition and discovered that the yeast equivalent of transcription elongation factor DSIF functions as a platform on transcribing RNA polymerase for recruitment of the Paf1C complex, thereby stimulating transcription-coupled histone H3 methylation.
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. The group recently characterized the mechanistic link between PKR kinase domain dimerization and eIF2α substrate recognition and revealed that the GTPase activity of the factor eIF5B is critical for release from the ribosome of both eIF5B and eIF1A following subunit joining.
Alexander Strunnikov's Unit on Chromatin Structure and Function is studying SMC protein complexes, particularly the role of the condensin complex in mitotic chromosome condensation and segregation. Recently, the Unit characterized targeting of condensin to specialized chromatin regions via genome-wide analysis. Studies also elucidated trans-controlling pathways responsible for the specificity of condensin binding to chromatins, particularly termination of DNA replication.
Henry Levin heads the Section on Eukaryotic Transposable Elements, which analyzes LTR retrotransposons and their mechanisms of reverse transcription, import of particles into the nucleus, and integration of cDNA. Recently, the laboratory demonstrated that the preferential insertion of Tf1 into the 5′ regions of genes results from the recognition of sequences within the promoter. In the case of the fbp1 promoter, the group found that the positions of integration were adjacent to a binding site for the transcription factor Atf1p. A mutation that blocked the binding of Atf1p greatly reduced integration, indicating that Atf1p was responsible for directing integration.
The Unit on Neuronal Connectivity, headed by Chi-Hon Lee, investigates the structure and development of color-vision circuitry in Drosophila. Recently, his group combined single-cell analysis and confocal imaging to map the first-order interneuons responsible for transmitting spectral information. The group also has identified two new loci involved in establishing connections between UV-sensitive photoreceptor neurons and their target interneurons.
The Section on Molecular Morphogenesis, headed by Yun-bo Shi, studies the gene-regulatory mechanisms involving thyroid hormone receptor (TR) that establish the developmental program of metamorphosis. The laboratory has demonstrated in vivo that gene activation by TR, through tissue- and gene-specific cofactor recruitment, is necessary and sufficient for metamorphosis. The group also revealed a critical role and a likely mechanism for the TR-regulated matrix metalloproteinase stromelysin-3 in tissue remodeling during metamorphosis.
Mary Dasso's Section on Cell Cycle Regulation also uses Xenopus laevis, in this case to study Ran GTPase and the SUMO family of ubiquitin-like proteins. During the past year, the group's studies on SUMO focused on the promyelocytic leukemia protein (PML), a major SUMO conjugation substrate that was first identified as a fusion protein in acute promyelocytic leukemia (APL) patients. The data indicate that PML may positively regulate SUMO conjugation and that such regulation may be altered by the genetic changes that induce APL. The group has further shown that the largest SUMO protease, SUSP1, acts preferentially on conjugated chains of SUMO-2 and SUMO-3 in a manner critical for maintenance of PML bodies within the nucleus.
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