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Landon L. Moore, Ph.D.
Assistant Professor of Genetics & Genomics
Ph.D. 1997, Purdue University
lmoore@bu.edu
Research Interests
Role of centromere three-dimensional structure in mitotic chromosome segregation
Figure 1. Holocentric chromosome screen for cin mutants. A wild-type holocentric chromosome (right) is shown with two chromosome instability (cin) mutants. These cin mutants assemble sister kinetochores twisted (left) or not resolved (right).
A prominent characteristic of human cancers and several genetic diseases, such as Fanconi anemia and Xeroderma pigmentosum, is chromosome instability. Centromere structure is important in preventing chromosome instability by assembling sister kinetochores such that they face in opposite directions (a back-to-back orientation). This orientation occurs during G2/early prophase and is dependent on the selective removal of chromatid cohesion from the CENP-A chromatin (centromere resolution). The regulated removal of cohesion is essential for chromosome stability: yet this process, at present, is not well understood. Caenorhabditis elegans was selected as the model system because it is genetically tractable and because centromeric activity throughout the mitotic chromosomes (holocentric) allows mutations in centromere structure to be easily distinguished (Figure 1). Because the whole mitotic chromosome is analogous to a centromere, we used holocentric chromosome structure to screen for mutants that affect the three-dimensional structure of centromeres. From both a classical genetic and a genome-wide RNAi screen we obtained several chromosome instability (cin) mutants. These mutants are currently under investigation in the lab.
Functional role for the catalytic domain of topoisomerase II in cohesin regulation
One of the mutants obtained from our screen, cin-4, is 89% identical to the catalytic domain of C. elegans topoisomerase II (top-2). Not surprisingly top-2 is required for chromosome structure as topoisomerase II is an enzyme that cleaves, manipulates, and rejoins DNA. Interestingly, cin-4, while a partial gene duplication of top-2, is required for a different function in organizing chromosome structure. We found that cin-4 is required for centromere resolution. In the absence of cin-4 function, cohesin is localized to sister kinetochores inhibiting their separation. The presence of cohesin alone is not sufficient to explain this inhibition. Removal of a cohesin dissociation pathway by WAPL-1 RNAi retains cohesin on mitotic chromosomes, but does not inhibit centromere resolution. These results together suggest that the catalytic domain of topoisomerase II interacts with cohesin in a different manner than the WAPL-1 pathway. Furthermore, this cin-4 mediated interaction has consequences for cohesion establishment and chromosome structure. Prior work has suggested a connection between topoisomerase II and cohesin, however the mechanism of this interaction is not understood. The presence of cin-4 in C. elegans as a duplication of the topoisomerase II catalytic domain with a specific role in cohesin regulation provides a unique opportunity to study the mechanism of topoisomerase II regulation of cohesin function.
Role of HCP-1 and HCP-2 in cell cycle regulation in response to stress
In collaboration with the lab of Dr. Pamela Padilla, we found that the gene HCP-1 and HCP-2 interact with the spindle assembly checkpoint differently. HCP-1 is the likely ortholog of CENP-F in C. elegans and HCP-2 is 54% similar to HCP-1. Prior work demonstrated that HCP-1 and HCP-2 are synthetic lethal. We found that HCP-1 and HCP-2 have distinct phenotypes when each is separately removed via RNAi or genetic mutation suggesting that each gene performs other functions in addition to their common function. We are currently investigating the unique functions of both HCP-1 and HCP-2.
publications
Hajeri, V. A., N. M. Stewart, L. L. Moore, P. A. Padilla (2008) Genetic Interactions Between the Spindle Checkpoint Genes and hcp-1 in Caenorhabditis elegans. Cell Division 2008, 3:6.
Stanvitch, G. and L.L. Moore (2008). cin-4, a gene with homology to topoisomerase II, is required for centromere resolution and cohesin removal from mitotic chromosomes. Genetics 178, 83-97.
Moore, L.L., G. Stanvitch, M.B. Roth, and D. Rosen (2005). HCP-4/CENP-C Promotes the Prophase Timing of Centromere Resolution by Enabling the Centromere Association of HCP-6 in Caenorhabditis elegans. Mol. Cell. Biol. 25: 2583- 2592.
Mishra, K. K., T.R. Holzer, L.L. Moore, and J.H. LeBowitz (2003). A negative regulatory element controls mRNA abundance of the Leishmania mexicana paraflagellar rod gene PFR2. Euk. Cell 2:1009-1017.
Moore, L. L., and M. B., Roth (2001). HCP-4, a CENP-C-like protein in C. elegans, is required for resolution of sister centromeres. J. Cell Biol. 153:1199-1207. reprint (518 KB, PDF)
Buchwitz, B.J., K. Ahmad, L.L. Moore, M.B. Roth, and S. Henikoff. (1999) A histone-H3-like protein in C. elegans. Nature. 401:547-548. reprint (212 KB, PDF)
Moore, L.L., M. Morrison, and M.B. Roth. (1999) HCP-1, a protein involved in chromosome segregation, is localized to the centromere of mitotic chromosomes in Caenorhabditis elegans. J Cell Biol. 147:471-480. reprint (325 KB, PDF)
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