Alan G. Hinnebusch, PhD, Chief

Five of the eight groups in the Laboratory of Gene Regulation and Development 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 by nutrient availability. Recently, the Section described the structural basis of autoinhibition and tRNA-mediated activation of the eIF2alpha kinase GCN2, provided evidence that activation of GCN2 by GCN1 occurs on translating ribosomes, and demonstrated a high degree of interdependence in recruitment of co-activators, an interdependence that distinguishes GCN4 from other transcriptional activators.

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 Section recently revealed the mechanistic link between kinase PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition, described the structure of the PKR-eIF2alpha complex, and identified molecular interactions within the GTP binding site that govern the ribosome-binding affinity of the factor eIF5B.

The Unit on Chromatin Transcription, headed by Rohinton Kamakaka, studies chromatin domain dynamics in yeast. Its studies on silenced chromatin domains has led the Unit to identify elements that block silencing, and the group has shown that several chromatin-remodeling proteins function in conjunction with the barrier elements to restrict the spread of silenced domains.

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 the targeting of condensin to specialized chromatin regions, using 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, the import of particles into the nucleus, and the integration of cDNA. Recently, the Section demonstrated that the preferential insertion of Tf1 into the 5' regions of genes results from the recognition of sequences within the promoter. The researchers also found that the sites of integration correspond closely with sites supersensitive to micrococcal nuclease, indicating that integration sites are positioned by promoter factors.

The Unit on Neuronal Connectivity, headed by Chi-Hon Lee, investigates the structure and development of color-vision circuitry in Drosophila. Recently, the Unit combined single-cell analysis and confocal imaging to map the first-order interneuons responsible for transmitting spectral information. The researchers also identified two new loci involved in establishing the connections between the UV-sensitive photoreceptor neurons and their target interneurons.

The Section on Molecular Morphogenesis, headed by Yun-bo Shi, studies the gene-regulatory mechanisms involving the thyroid hormone receptor (TR) that establish the developmental program of metamorphosis in the anuran Xenopus laevis. The Section has demonstrated in vivo that gene activation by TR, through tissue- and gene-specific co-factor recruitment, is necessary and sufficient for metamorphosis. The researchers also revealed a critical role and 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 to study the Ran GTPase and the SUMO family of ubiquitin-like proteins. The group has shown that the SUMO-1–dependent targeting of the Ran-activating protein (RanGAP1) and its binding partner (RanBP2) to mitotic mammalian kinetochores is essential for correct kinetochore fiber assembly. The Section documented a novel mechanism of RanBP2/RanGAP1 targeting to kinetochores in mammalian cells that uses Crm1, a nuclear export receptor. In addition, the researchers showed that conjugation of SUMO-2 to mitotic chromosomal substrates, including topoisomerase-II, is critical to correct chromosomal segregation during anaphase.