Associate Professor, Molecular and Cellular Biology
Associate Professor, BIO5 Institute
Associate Head, Faculty Development
Associate Professor, Cancer Biology - GIDP
Associate Professor, Genetics - GIDP
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.
Dr. Rogers' 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. Dr. Rogers' 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.
2010 Joseph S. Pagano Postdoctoral Award – UNC Lineberger Cancer Center
2009-2010 Arizona Cancer Center SPORE in GI Cancer Career Development Award
2009-2010 American Cancer Society Institutional Research Grant Award
1997-1998 Jastro-Shields Graduate Research Award
1996-1998 Molecular and Cellular Biology NIH Graduate Training Grant
1994 Cum Laude, General Honors, University of Rochester
1993 Die Kiewet Undergraduate Summer Research Fellowship
1991-1994 University of Rochester Undergraduate Scholarship