Heads of Laboratories
During mitosis, a full set of chromosomes must be equally distributed to the offspring of each dividing cell, and failure to do so can result in numerous disorders, including birth defects and tumor progression. The Funabiki lab studies how chromosomes signal to spatially and temporally orchestrate a precise series of mitotic events to ensure accurate chromosome segregation.
A mitotic cell undergoes a series of dramatic morphological changes, including chromosome condensation, spindle formation, chromosome segregation and cytokinesis. These events must occur at the right place, at the right time, in the right order. In particular, the Funabiki lab studies:
Spatial control of chromosome-induced signals during spindle formation. The Funabiki lab demonstrated that mitosis-specific phosphorylation of histone H3, the major component of chromosomes, is vital in formation of the spindle, a cellular apparatus to segregate chromosomes. They found that Survivin, whose expression is implicated in cancer development, binds histone H3 that is phosphorylated at the threonine 3 residue (H3T3ph). This binding results in recruitment and activation of the kinase Aurora B, which leads to spindle assembly around chromosomes. They are now trying to understand the mechanistic basis for the kinase activation upon binding to H3T3ph and the resulting spindle assembly.
Temporal control that converts the chromosome-induced signals into different intracellular architectures. At the end of mitosis, chromosomes must stop supporting the spindle assembly and initiate nuclear envelope assembly. This dramatic conversion of chromosome-assisted intracellular architecture is mediated in part by silencing the Aurora B activity on chromosomes. However, the nuclear envelope should not reform before completion of chromosome segregation; thus the timing of this conversion must be accurately controlled. The Funabiki lab has shown that dephosphorylation of H3T3ph plays a key role in this process, and they are now studying how the activity of H3T3 kinase, Haspin, is regulated during the cell cycle. Furthermore, the lab is investigating a novel chromosome-binding protein, which is specifically conjugated with ubiquitin-like protein, SUMO, upon binding chromosomes and opposes the function of Aurora B. Through these studies, Dr. Funabiki aims to understand the mechanisms by which the precise order of events at the exit from mitosis is controlled.
Mechanical control that transduces microtubule attachment into the chemical signal to permit chromosome separation. In order to segregate chromosomes, microtubules must attach to the proteinaceous structure, the kinetochore, which is built on each centromere of chromosomes. Importantly, until all the kinetochores attach to microtubules in the right orientation, unattached kinetochores activate the signaling pathway called the “spindle assembly checkpoint” to delay sister chromatid separation and exit from mitosis. Collaborating with Rockefeller’s Fred Cross, Dr. Funabiki discovered that the protein phosphatase 1 at the kinetochore is critical for silencing the checkpoint upon microtubule attachment. They aim to understand the mechanism by which the phosphatase converts the microtubule attachment event into the checkpoint silencing.
Roles of histone modifications during mitosis. Upon entry into mitosis, chromosomes show dramatic structural changes accompanied with histone phosphorylation. The functional significance of mitotic histone phosphorylation remains largely unclear. The Funabiki lab aims to develop a method to examine the role of histone modification using frog egg extracts.
Impact of DNA structural changes. Collaborating with Rockefeller’s Brian Chait, the Funabiki lab developed a proteomic method to identify proteins and modifications that specifically associate with DNA with double-strand breaks. Using this method, the lab identified a novel ubiquitin-mediated pathway to remove DNA-damage repair protein and also identified SMARCAL1, whose mutation is responsible for Schimke immuno-osseous dysplasia, a multisystem autosomal recessive disorder.
Dr. Funabiki received his bachelor’s degree in chemistry in 1990 and his Ph.D. in cell biology in 1995, both from Kyoto University in Japan. From 1996 until 2000, he worked as a postdoc in the physiology department at the University of California, San Francisco, and then at Harvard University as a postdoc in molecular and cellular biology. He came to Rockefeller as an assistant professor and head of the Laboratory of Chromosome and Cell Biology in 2002 and was promoted to associate professor in 2007.
Dr. Funabiki received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award and the Irma T. Hirschl/Monique Weill-Caulier Trusts Research Award in 2003. He received the Searle Scholar Award from the Chicago Community Trust in 2002. He was a special fellow of the Leukemia and Lymphoma Society from 1999 to 2002 and a Leukemia and Lymphoma Society fellow from 1996 to 1999.
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