Heads of Laboratories
Tri-Institutional Associate Professor
Associate Professor
Laboratory of Chromosome and Cell Biology
funabiki@rockefeller.edu
A dividing cell must accurately distribute a full set of chromosomes to each daughter cell, and failure to do so can result in numerous disorders, including birth defects and tumor progression. Dr. Funabiki is interested in the molecular processes that regulate the structure and configuration of chromosomes during the cell division cycle. Using frog egg extract as a model system, he is investigating how cells developed the elaborate mechanisms that control their accurate reproduction.
For cells to accurately maintain their genome information, they must ensure that their chromosomes are equally segregated when they divide. The chromosomes must be condensed, captured by the dynamic microtubules that serve as the cell’s supportive skeleton, then aligned at the equator of the bipolar spindle — events that are temporally and spatially controlled by a subset of microtubuleand chromatin-associated proteins. Dr. Funabiki’s laboratory is combining methods from biochemistry, cell biology and biophysics in order to study this process, in particular how the dynamic chromosome structure can create, maintain and propagate signals.
The Funabiki lab uses the Xenopus laevis (African clawed frog) egg extract system, which provides a unique experimental setup for studying mitosis. The system recapitulates a number of in vivo processes (e.g., DNA replication, spindle assembly and chromosome segregation), but its in vitro nature allows a direct correlation between morphological events and their biochemical properties. Using immunodepletion, Dr. Funabiki can study the specific function of a protein and then reintroduce wild-type or mutant versions to the extract. He can also add DNA in the form of entire chromosomes or particular structures or sequences to investigate specific aspects of these cellular processes.
The major focus of the Funabiki lab is chromosome-induced spindle assembly. During mitosis, microtubules are extremely dynamic and unstable but chromosomes can locally promote microtubule and spindle assembly. They have the capacity to assemble a bipolar spindle in cells with a wide range of shapes and sizes. This ability is particularly important in the female meiotic cells of many animals, which are significantly larger than chromosomes and lack centrosomes, yet in which spindle microtubule formation is still restricted to chromosomes. Through systematic identification of novel chromosome-binding proteins, the Funabiki lab identified Dasra, a new member of the chromosomal passenger complex (CPC), which also contains Incenp, Survivin and the kinase Aurora B, and discovered that the CPC is essential for this chromosome-induced spindle assembly. They have also recently shown that the Aurora B pathway is suppressed by phosphatases in the cytoplasm but that chromosomes can activate it. His group is now studying the mechanism by which chromosomes activate the Aurora B pathway, and how the CPC and other chromosome-binding proteins modulate microtubule-chromosome interactions to ensure that the chromatids segregate equally to daughter cells during cell division. Another interest of the Funabiki lab is the role of histone modifications in mitosis. Histones are major substrates for posttranslational modifications during mitosis, but their roles remain unclear. Collaborating with Rockefeller’s C. David Allis, the Funabiki lab showed that the phosphorylation of histone H3 by Aurora B is important for dissociation of heterochromatin protein 1 (HP1) from metaphase chromosomes, as it weakens the interaction between HP1 and its recognition motif. The lab continues to investigate the biological significance of histone modifications during mitosis.
The last area of focus for the Funabiki lab is DNA structural changes — understanding how they are recognized and how this recognition generates a variety of downstream signals. His lab uses double-stranded DNA breaks as a model structure to determine what type of protein modifications are stimulated by this DNA damage. In collaboration with Rockefeller’s Brian T. Chait, the Funabiki lab is using mass spectrometry to identify proteins and protein modifications that are specifically associated with doublestrand DNA breaks. Recently, they discovered a novel DNA-damage-induced ubiquitylation pathway that regulates removal of the damage repair proteins.
CAREER
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 Trust 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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