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Professor RESEARCH
Our
laboratory is interested in understanding how the cell cycle is regulated in
the context of organismal development. We are using the nematode Caenorhabditis
elegans as a model system. The adult C. elegans has only 959
somatic cells, yet has multiple tissues, including muscle, skin, neurons, and
intestine. Somatic cell divisions are developmentally programmed and largely
invariant, thereby allowing detailed analysis of individual cell divisions
through development. We are
currently focusing on understanding the functions of the cullin/RING finger
class of ubiquitin-protein ligases, whose members target the
ubiquitin-mediated degradation of a diverse set of substrates, including cell
cycle regulators. Cullin/RING finger complexes comprise a core that includes
cullins and RING finger proteins. The cullin gene family contains five major
branches in metazoa. Our laboratory is currently exploring the in vivo
functions of the C. elegans cullins CUL-1, CUL-2, and CUL-4. CUL-1 functions
as a negative cell cycle regulator, which is required for cell cycle exit. In
the absence of CUL-1, dividing cells are unable to respond to developmental
cues to exit the cell cycle, and instead continue to proliferate thereby
producing hyperplasia. CUL-2, in contrast, is a positive cell cycle regulator
that is required for a number of different cell cycle events: G1 phase
progression, chromatin condensation, and mitotic and meiotic progression.
Finally, CUL-4 functions as a negative regulator of DNA replication that acts
to restrict DNA replication licensing. Our current projects involve both genetic and biochemical approaches to identify the substrates that must be ubiquitinated to allow the cullin-dependent cell cycle events to occur. We are also characterizing the proteins components in the cullin/RING finger complexes that are responsible for the observed cellular functions, as we expect multiple substrate-binding components will be present for each core complex. These studies on understanding basic aspects of cell cycle regulation will help to lay the foundation for the more long-range, comprehensive goal of understanding of how the cell cycle is regulated through development.
SUPPORT STAFF
REPRESENTATIVE PUBLICATIONS
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