Faculty Research Page
Bowes Research FellowLab Homepage: http://mcb.berkeley.edu/labs/holt/
Humans, starfish, worms, mushrooms and trees all evolved from a common ancestor. The ancestral organism was unicellular and had an information processing system that controlled cell division. This division signaling network instructed cells to divide whenever possible.
Multicellular animals establish their body-plan during embryogenesis. Embryonic cells must divide with a high degree of spatial and temporal organization. The cells have to divide at the right time and in the right direction to form a human or a starfish. Furthermore, once the adult organism is formed, cells must stop dividing to prevent deformation of the structure of organs.
The human and starfish control networks have evolved from the ancestral network by modification and elaboration. For example, subroutines have been added that process spatial information during embryogenesis and prevent deleterious cell division in the adult. When these subroutines break down, our cells revert to the ancestral program: divide whenever possible. This uncontrolled division leads to cancer.
We study the rewiring of cell division control networks: How does the program change in evolution? How can the program be changed synthetically?
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Figure 1. Plasticity in transcriptional regulation and phosphoregulation.
Just as simple response elements are more likely to arise by small numbers of mutations in relatively unconstrained intergenic regions (promoters or introns, a), phosphorylation sites are more likely to appear in disordered regions of proteins (termini or long loops, b). Context-independent mechanisms of activity modulation seem to predominate in both forms of regulation, allowing for relatively easy evolution of regulation. In the example presented here, combinatorial regulation by two distinct transcription factors or kinases creates an ‘OR’ logic gate (c).
1. Synthetic biology approaches to understanding general principles of regulation
Reengineering of phosphorylation control to try to find general principles of regulation
2. Directed evolution to discover new signaling pathways
Applying strong selection to anaphase control networks and analysing evolved strains with whole genome sequencing technologies
3. Understanding the evolution of complexity
How is the single mitotic division elaborated to a double meiotic division?
Holt, LJ*, Tuch, BB*, Villén, J*, Johnson, AD, Gygi, SP & Morgan, DO (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution Science, 2009 Sep 25;325(5948):1682-6
Holt LJ, Krutchinsky, AN, Morgan, DO Positive Feedback Sharpens the Anaphase Switch. Nature, 2008, Jun 15, 454(7202):353-7
Holt LJ, Hutti, J, Cantley, L, Morgan, DO Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell. 2007 Mar 9;25(5):689-702
* Indicates equal contribution
Last Updated 2011-05-12