Five of the eight groups in the Laboratory of Gene Regulation and Development study gene regulation and chromosome structure in the unicellular eukaryotes Saccharomyces cerevisiae and Schizosaccharomyces pombe. Having shown previously that four eukaryotic translation initiation factors (eIFs 1, 2, 3, and 5) reside in a multifactor complex with an important function in translation initiation, the section headed by Alan Hinnebusch recently identified independent contacts between eIF2 and eIF3 in the multifactor complex that make additive contributions to a critical step in the pathway downstream from 48S complex assembly. The researchers also showed that the kinase GCN2, which regulates translation by phosphorylating eIF2, is controlled by the TOR signalling pathway. Another section of the laboratory, headed by Thomas Dever, is characterizing several eIFs and the protein kinases that regulate eIF2 activity, focusing on principles of kinase-substrate recognition. The team determined that GTP binding induces structural rearrangements in the universally conserved translation initiation factor eIF5B/IF2, which regulates the factor’s affinity for the ribosome.

Gene silencing in yeast is the focus of a unit, headed by Rohinton Kamakaka, that characterizes Sir2 protein complexes and recently demonstrated a role for histone Htz1 in cell-cycle progression and silencing. The unit also identified proteins involved in chromatin remodeling that have the ability to impede the spread of silenced chromatin. Another unit, headed by Alexander Strunnikov, is investigating the molecular mechanisms of chromosome condensation (condensin complex) and sister chromatid cohesion (cohesin complex). The group recently dissected the role of post-translational modifications in the regulation of condensin and reconstituted the cohesin-chromatin interaction in vitro and began dissecting the molecular nature of SMC complexes in bacteria.

The section headed by Henry Levin is analyzing a retrotransposon that is structurally related to mammalian retroviruses. The section recently identified residues in reverse transcriptase that are required for removal of the RNA primer from the completed cDNA as a prerequisite for integration and also identified two host factors required for Tf1 transposition, a methyltransferase that methylates lysine 4 of histone H3 and a factor that mediates vesicle traffic.

The newly formed unit headed by Chi-Hon Lee investigates the molecular basis of connection specificity in the Drosophila visual system, focusing on N-cadherin function. The group recently discovered that N-cadherin loci undergo alternative splicing to generate multiple isoforms and suggested that combinatory use of these isoforms provides a “synaptic code” for matching pre- and post-synaptic partners.

The anuran Xenopus laevis serves as a model system for the remaining two groups. The unit headed by Yun-Bo Shi studies the role of thyroid hormone (TH) and its receptor (TR) during metamorphosis and the functions of matrix metalloproteinases (MMPs) induced by TR in organ remodeling. The group recently demonstrated that unliganded TR recruits to TH-response gene corepressors that in turn recruit histone deacetylases in order to repress gene expression in premetamorphic tadpoles, that transgenic overexpression of a dominant negative TR blocks the expression of TH-response genes and metamorphosis, and that the MMP stromelysin-3 is required for TH-induced apoptosis in the intestine. Mary Dasso’s group studies the small ubiquitin-like protein SUMO-1 and recently showed that SUMO-1 conjugation and deconjugation enzymes localize to opposite sides of the nuclear pore in mammals. The researchers also demonstrated that SUMO-1 conjugation regulates the mitotic localization of the GTPase-activating protein (RanGAP1) for Ran, a GTPase that is essential for nuclear transport in all eukaryotes.