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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. |