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Laboratory of Chromosome and Cell Biology

Hironori Funabiki
Professor
Tri-Institutional Professor

Motivation of the lab

by Michael WheelockWe are composed of trillions of cells, which are all derived from a single egg cell. After fertilization, this one cell, containing 46 chromosomes (23 from your mother and 23 from your father), divides a number of times to make up a fully formed human being with trillions of cells. Even in adults, billions of cells are generated each date to replenish dying cells. Except for matured red blood cells, which lack a nucleus, and other specialized cells, most of those cells maintain the same original set of 46 chromosomes. Therefore, a number of mechanisms engage to ensure that each replicated chromosomes are equally distributed to daughter cells every time when a cell divides. However, in most cancer cells, the number and the composition of this chromosome set are drastically changed from the norm. Accumulating lines of evidence strongly suggest that the mechanism supporting the proper chromosome segregation is compromised in those cancer cells, contributing to tumor development.

The long-term goals of the Funabiki lab are:

  1. To understand the molecular mechanisms and principles that ensure proper chromosome segregation during mitosis.
  2. To understand the mechanism that causes chromosome missegregation in cancer cells.
  3. To understand how chromosome missegregation contributes to tumorigenesis.
  4. To help design therapeutic approaches to selectively eliminate cancer cells without harming most normal cells.

Ongoing projects

Our laboratory is interested in the mechanisms controlling the spatial and temporal control of mitosis; in particular, how the dynamic chromosome structure can create, maintain, and propagate the signals to control mitosis. We combine biochemical, cell biological and biophysical methods to approach these questions.

  1. Mechanisms that control microtubule assembly and interaction with chromosomes.

    Directional chromosome movement during mitosis depends on assembly of dynamic microtubule polymers around chromosomes, and on attachment of microtubule ends in the correct orientation to the kinetochore apparatus, which forms the centromere locus of each chromosome. We aim to understand the molecular mechanisms that ensure accurate chromosome segregation, focusing on mechanistic dissection of the chromosomal passenger complex (CPC), which contains the protein kinase Aurora B and regulates a variety of mitotic processes including microtubule dynamics, kinetochore assembly, and kinetochore-microtubule attachment.

  2. Regulation of size, shape, and functions of chromosomes during mitosis

    Chromosomes in interphase are relatively decondensed and support DNA replication and transcription during interphase. In contrast, mitotic chromosomes are more condensed and individualized to support chromosome segregation. Moreover, chromosomes in interphase stimulate distinct signals to assemble the nuclear envelope, but in mitosis, the nuclear envelope breaks down and chromosomes promote assembly of the spindle microtubules. We aim to understand molecular mechanisms behind these structural and functional changes of chromosomes at the cell cycle transitions between interphase and mitosis.

  3. Mechanisms that maintain centromere integrity

    Human centromeres are composed of large tandem arrays of alpha-satellite repetitive DNA elements, spanning up to ~ 5 Mb in size. Our recent results indicate that this repetitive organization becomes unstable in cancer cells and during replicative senescence. In addition, arrays of satellite 2 and 3 repeats at juxtacentromere of chromosome 1 and 16 are fragile in Immunodeficiency–Centromeric instability–Facial anomalies (ICF) syndrome. Underlining mechanisms behind the ICF syndrome is poorly understood.

  4. Consequences of aberrant mitosis and chromosome missegregation

    Many cancer cells exhibit a “chromosome instability (CIN)” phenotype, where chromosomes frequently fail to equally distribute to daughter cells. How chromosome missegregation contributes to tumorigenesis remains unclear. In addition, anti-microtubule drugs, such as taxol, which cause mitotic arrest and chromosome missegregation, are commonly used to treat breast and other cancers but their underlining mechanism is not established. We hypothesize that the innate immune system, which normally responds to pathogenic DNAs, senses aberrant mitosis and affect fates.

     

    Postdoc position available (last updated September 2017)
    The Funabiki lab has open positions for postdoctoral researchers willing to execute projects related to chromosome segregation machineries and consequences of chromosome missegregation. We seek those who are willing to pursue a wide range of questions, from the structural to the systems level. Besides those who have background in mitosis and genome integrity, we also welcome those who come from different research areas but have training in biophysics, structural biology, cutting-edge imaging technologies, a large-scale sequence analysis, cancer biology or immunology.

    Applications can be sent via email to funabih@rockefeller.edu with CV, a summary of past research experience, potential future research directions, and a list of references with contact information.

Hironori FunabikiProfessorTri-Institutional ProfessorMotivation of the labWe are composed of trillions of cells, which are all derived from a single egg cell. After fertilization, this one cell, c