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The overall goals of Dr. Rogers' research program are 1) to understand how centrosomes assemble and how their duplication is regulated, 2) to understand how the 3-dimensional organization of the nucleus controls gene expression, and 3) to understand how genomic instability contributes to cancer, birth defects and aging-related diseases. In regard to centrosome (or centriole) duplication, errors in this process can result in centriole amplification which directly promotes chromosomal instability, leading to tumorigenesis and birth defects. Importantly, the molecular alterations in cancer that promote centriole amplification are unknown. Regarding aging-related diseases, mutations in nuclear lamina proteins disrupt nuclear architechure and normal gene expression leading to early aging onset syndromes such as progeria. In pursuit of his goals, his laboratory employs a multifaceted approach – genetic, functional genomic, cell biology, protein structure, and biochemical strategies. The centerpiece of their research is a conserved regulator of chromatin structure, condensin II. In this proposal, they build upon their discovery that condensin II functions to drive chromosome territory (CT) formation and that its stabilization (or hyperactivation) leads to defects in nuclear envelope morphology that is strikingly similar to nuclei in cells derived from Hutchinson-Gilford progeria syndrome patients (Buster et al., J. Cell Biol., 2013).
Dr. Rogers' postdoctoral training at the Albert Einstein College of Medicine in the laboratory of David Sharp and at the University of North Carolina (Chapel Hill) in the laboratory of Stephen Rogers as well as establishing his laboratory at the University of Arizona over the last 7 years has allowed him to develop an independent research program and the expertise required for the successful execution of this proposal. Much of their research stems from the Drosophila system, and his training focused on the cell biology of dividing cells in model organisms. During this time, they characterized microtubule-based motors and associated proteins in coordinating mitotic spindle assembly. They also made several important discoveries that identified the mechanisms of anaphase chromosome segregation and poleward microtubule flux in the spindle (Rogers et al., Nature, 2004).
As a postdoc fellow at UNC, Dr. Rogers' interests turned to mechanisms of spindle bipolarity and he focused on how cells control centriole number, which led to the foundation for his research program at the University of Arizona. During this time, he identified a new regulatory pathway for Plk4 and characterized this kinase as a licensing factor for centriole duplication (Rogers et al., J. Cell Biol., 2009), breaking through an intellectual logjam in the field and preparing the way to further explore the molecular basis of the duplication event.
In Dr. Rogers' lab, they have published several studies focused on the regulation of centriole duplication. They discovered the first mechanisms that activate Plk4, a mechanism exploited by SV40 DNA tumor-promoting virus (Brownlee et al., J. Cell Biol., 2011; Klebba et al., 2015). They also found that Plk4 generates its own phosphodegron to promote its own destruction (Klebba et al., Curr. Biol., 2013).
In collaboration with Kevin Slep (UNC), they have solved the atomic structure of the his sterious Plk4 cryptic polo box, revealing a new structural feature of this kinase family (Slevin et al., Structure, 2012). They have also identified the first function of the C-terminal Polo Box in Plk4 which functions to relieve a previously unknown autoinhibition mechanism (Klebba et al., PNAS, 2015). In collaboration with David Bilder (UCB) and Giovanni Bosco (Dartmouth College), they have expanded their studies of ubiquitin-mediated regulation to nuclear organization and they recently discovered a new pathway for condensin II regulation (Buster et al., J. Cell Biol., 2013), that may contribute to a host of laminopathies in humans.
In summary, Dr. Rogers has demonstrated that he has a productive, independent research program. In April 2014, he received tenure and attained the rank of Associate Professor. He is confident that they will be able to successfully accomplish the Aims of this research proposal.
My laboratory is interested in the molecular mechanisms cells use to maintain stability of their genomes. This is medically relevant because genomic instability can promote tumorigenesis. During mitosis, cells face particular risk, as errors in chromosome segregation can lead to chromosome instability (CIN) which is characterized, in part, by an abnormal chromosome complement (known as aneuploidy). Indeed, aneuploidy promotes malignant transformation and is an underlying cause of birth defects. Mitotic spindles are used to faithfully segregate chromosomes into daughter cells and, for this to occur properly, it is critical that cells assemble spindles with a bipolar fusiform-shape. Cells control spindle shape using centrosomes, tiny organelles that nucleate the microtubule cytoskeleton and organize the two spindle poles. Normally, cells contain a single centrosome which duplicates once per cell cycle, thus ensuring that cells enter mitosis with only two centrosomes to build a bipolar spindle. Cancer cells, however, overduplicate their centrosomes, which leads to multipolar spindle formation and chromosome instability. In fact, most human tumors contain cells with elevated centrosome numbers and aneuploid genomes. Importantly, the fundamental mechanisms that cells use to control their centrosome number are unclear, nor is it understood how this regulation goes awry in cancer. My work centers on characterizing a particular pathway (the Plk4 pathway) to control the biogenesis of centrosomes. This pathway utilizes both phosphorylation and ubiquitin-mediated proteolysis as regulatory mechanisms in a complex signaling pathway to control the biogenesis of centrosomes.
- Wallace, H.A., Klebba, J.E., Kusch, T., Rogers, G.C. and Bosco, G. (2015) Condensin II regulates interphase chromatin organization through the Mrg15 binding motif of Cap-H2. G3: Gene/Genomes/Genetics. doi: 10.1534/g3.115.016634 [Epub ahead of print].
- Nguyen, H.Q., Nye, J., Buster, D.W., Klebba, J.E., Rogers, G.C.* and Bosco, G.* (2015) Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels. *co-corresponding authors. PLoS Genetics. 11, e1005014. doi: 10.1371/jouranl.pgen.1005014.
- Klebba, J.E., Galletta, B., Nye, J., Plevock, K., Buster, D.W., Hollingsworth, N.A., Slep, K.C., Rusan, N.M.* and Rogers, G.C.* (2015) Two Polo-like kinase 4 binding domains in Asterless play antagonistic roles in regulating kinase stability. Journal of Cell Biology. *co-corresponding authors. 208, 401-414.
- Klebba, J.E., Buster, D.W., McLamarrah, T.A., Rusan, N.M. and Rogers, G.C. (2015) Autoinhibition and relief mechanism for Polo-like kinase 4. Proceedings of the National Academy of Sciences USA. 112, E657-666.
- Bozler, J., Nguyen, H.Q., Rogers, G.C. and Bosco, G. (2014) Condensins exert force on chromatin-nuclear envelope tethers to mediate nucleoplasmic reticulum formation in Drosophila melanogaster. G3: Genes/Genomes/Genetics. 5, 341-352.
- Skwarek, L.C., Windler, S.L., de Vreede, G., Rogers, G.C., and Bilder, D. 2014. The F-box protein Slmb restricts activity of aPKC to polarize epithelial cells. Development. 141, 2978-2983.
- Galletaa, B.J., Guillen, R.X., Fagerstrom, C.J., Brownlee, C.W., Lerit, D.A., Megraw, T., Rogers, G.C., and Rusan, N.M. 2014. Drosophila Pericentrin requires interaction with Calmodulin for its function at centrosomes and neuronal basal bodies, but not at sperm basal bodies. Molecular Biology of the Cell. 25, 2682-2694.
- Nye, J., Buster, D.W. and Rogers, G.C. 2014. The use of cultured Drosophila cells for studying the microtubule cytoskeleton. Methods in Molecular Biology. 1136, 81-101.
- Klebba, J.E., Buster, D.W., Nguyen, A.L., Swatkoski, G., Gucek, M., Rusan, N.M., and Rogers, G.C. 2013. Polo-like kinase 4 autodestructs by generating its Slimb-binding phosphodegron. Current Biology. 23, 2255-2261.
- Smith, H. F., Roberts, M.A., Nguyen, H.Q., Peterson, M., Hartl, T.A., Wang, X.J., Klebba, J.E., Rogers, G.C. and Bosco, G. 2013. Maintenance of interphase chromosome compaction and homolog pairing in Drosophila is regulated by the condensin Cap-H2 and its partner Mrg15. Genetics. 195, 127-46.
- Buster, D.W., Daniel, S.G., Nguyen, H.Q., Windler, S.L., Skwarek, L.C., Peterson, M., Roberts, M., Meserve, J.H., Hartl, T., Klebba, J.E., Bilder, D., Bosco, G. and Rogers, G.C. 2013. SCFSlimb ubiquitin-ligase suppresses condensin II-mediated nuclear reorganization by degrading Cap-H2. Journal of Cell Biology. 201, 49-63.
- Brownlee, C.W. and Rogers, G.C. 2013. Show me your license, please: deregulation of centriole duplication mechanisms that promote amplification. Cellular and Molecular Life Sciences. 70, 1021-1034.
- Mennella, V., Keszthelyi, B., McDonald, K.L., Chhun, B., Kan, F., Rogers, G.C., Huang, B. and Agard, D.A. 2012. Subdiffraction-resolution fluorescence microscopy reveals a domain of the centrosome critical for pericentriolar material organization. Nature Cell Biology. 14, 1159-1168.
- Slevin, L.K., Nye, J., Pinkerton, D.C., Buster, D.W., Rogers, G.C.* and Slep, K.C.* 2012. The structure of the Plk4 cryptic polo box reveals two tandem polo boxes required for centriole duplication. Structure. 20, 1905-17. *co-corresponding authors.
- Roberts, D.M., Pronobis, M.I., Alexandre, K.M., Rogers, G.C., Poulton, J.S., Schneider, D.E., Jung, K.C., McKay, D.J. and Peifer M. 2012. Defining components of the ß-catenin destruction complex and exploring its regulation and mechanisms of actin during development. PLoS One. 7(2):e31284. doi: 10.1371
- Brownlee, C.W., Klebba, J.E., Buster, D.W. and Rogers, G.C. 2011. The Protein Phosphatase 2A regulatory subunit Twins stabilizes Plk4 to induce centriole amplification. Journal of Cell Biology. 195, 231-243.
- Taylor, S.M., Nevis, K.R., Park, H.L., Rogers, G.C., Rogers, S.L., Cook, J.G. and Bautch, V.L. 2010. Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels. Blood. 116, 3108-3117.
- Buster, D.W., Nye, J., Klebba, J.E. and Rogers, G.C. 2010. Preparation of Drosophila S2 cells for light microscopy. Journal of Visualized Experiments. doi: 10.3791/1982.
- Rogers, G.C. 2010. More than just microtubules: actin-dynamics separate interphase-prophase centrosomes. Current Biology. 20, R364-R366.
- Rath, U., Rogers, G.C., Tan, D., Gomez-Ferreria, M.A., Buster, D.W., Sosa, H.J. and Sharp, D.J. 2009. The Drosophila kinesin-13, KLP59D, impacts Pacman and Flux-based chromosome movement. Molecular Biology of the Cell. 20, 4696-4705.
- Rusan NM, Rogers GC. 2009. Centrosome function: Sometimes less is more. Traffic, 10, 472-481.
- Rogers GC, Rusan NM, Roberts DM, Peifer M, Rogers SL. Jan 2009. The SCF Slimb ubiquitin ligase regulates Plk4/Sak levels to block centriole reduplication. J Cell Biol, 184:225-39
- Hall, J.R., Lee, H.O., Bunker, B.D., Dorn, E.S., Rogers, G.C., Duronio, R.J. and Cook, J.G. 2008. Cdt1 and Cdc6 are destabilized by rereplication-induced DNA damage. Journal of Biological Chemistry. 283, 25356-63.
- Rogers GC, Rusan NM, Peifer M, Rogers SL. Jul 2008. A multicomponent assembly pathway contributes to the formation of acentrosomal microtubule arrays in interphase Drosophila cells. Mol Biol Cell, 19:3163-78
- Rogers SL, Rogers GC. Dec 2007. Culture of Drosophila S2 cells and their use for RNAi-mediated loss-of-function studies and immunofluorescence microscopy. Nat Protoc, 3:606-11
- Zhang D, Rogers GC, Buster DW, Sharp DJ. Apr 2007. Three microtubule severing enzymes contribute to the "Pacman-flux" machinery that moves chromosomes. J Cell Biol, 177:231-42
- Kim H, Ling SC, Rogers GC, Kural C, Selvin PR, Rogers SL, Gelfand VI. Feb 2007. Microtubule binding by dynactin is required for microtubule organization but not cargo transport. J Cell Biol, 176:641-51
- Rogers GC, Rogers SL, Sharp DJ. Mar 2005. Spindle microtubules in flux. J Cell Sci, 118:1105-16
- Mennella V, Rogers GC, Rogers SL, Buster DW, Vale RD, Sharp DJ. Mar 2005. Functionally distinct kinesin-13 family members cooperate to regulate microtubule dynamics during interphase. Nat Cell Biol, 7:235-45
- Sharp, D.J. and Rogers, G.C. (2004) A Kin-I-dependent Pacman-flux mechanism for anaphase A. Cell Cycle. 3, 707-710.
- Rogers GC, Rogers SL, Schwimmer TA, Ems-McClung SC, Walczak CE, Vale RD, Scholey JM, Sharp DJ. Jan 2004. Two mitotic kinesins cooperate to drive sister chromatid separation during anaphase. Nature, 427:364-70
- Kwon, M., Brust-Mascher, I., Morales-Mulia, S., Rogers, G.C., Sharp, D.J. and Scholey, J.M. (2004) The chromokinesin, KLP3A, drives mitotic spindle pole separation during prometaphase and anaphase, and facilitates chromatid motility. Molecular Biology of the Cell. 15, 219-233.
- Rogers SL, Rogers GC, Sharp DJ, Vale RD. Sep 2002. Drosophila EB1 is important for proper assembly, dynamics, and positioning of the mitotic spindle. J Cell Biol, 158:873-84
- Rogers, G.C., Rogers, S.L., Sharp, D.J. and Scholey, J.M. (2002) Dynein. Wiley. Encyclopedia of Molecular Medicine. Vol. 2, pp 1108-1116 (New York: John Wiley & Sons).
- Scholey JM, Rogers GC, Sharp DJ. Jul 2001. Mitosis, microtubules, and the matrix. J Cell Biol, 154:261-6
- Chui, K.K., Rogers, G.C., Kashina, A.M., Wedaman, K.P., Sharp, D.J., Nguyen, D.T. and Scholey, J.M. (2000) Roles of two homotetrameric kinesins in sea urchin embryonic cell division. Journal of Biological Chemistry. 275, 38005-38011.
- Sharp DJ, Rogers GC, Scholey JM. Dec 2000. Cytoplasmic dynein is required for poleward chromosome movement during mitosis in Drosophila embryos. Nat Cell Biol, 2:922-30
- Sharp DJ, Rogers GC, Scholey JM. Sep 2000. Microtubule motors in mitosis. Nature, 407:41-7
- Rogers GC, Chui KK, Lee EW, Wedaman KP, Sharp DJ, Holland G, Morris RL, Scholey JM. Aug 2000. A kinesin-related protein, KRP(180), positions prometaphase spindle poles during early sea urchin embryonic cell division. J Cell Biol, 150:499-512
- Sharp, D.J., Rogers, G.C. and Scholey, J.M. (2000) Roles of motor proteins in building microtubule-based structures: a basic principle of cellular design. Biochimica et Biophysica Acta. 1496, 128-141.
- Sharp, D.J., Brown, H.M., Kwon, M., Rogers, G.C., Holland, G. and Scholey, J.M. (2000) Functional coordination of three mitotic motors in Drosophila embryos. Molecular Biology of the Cell. 11, 241-253.
- Rogers, G.C., Hart, C.L., Wedaman, K.P. and Scholey, J.M. (1999) Identification of Kinesin-C, a calmodulin-binding carboxy-terminal kinesin in animal (Strongylocentrotus purpuratus) cells. Journal of Molecular Biology. 294, 1-8.
- Kashina, A.S., Rogers, G.C. and Scholey, J.M. (1997) The bimC family of kinesins: essential bipolar mitotic motors driving centrosome separation. Biochimica et Biophysica Acta. 1357, 257-271.