Experiments Decipher Key Piece of the ‘histone Code’ In Cell Division
ScienceDaily (Sep. 22, 2010) — Reproduce or perish. That's the bottom line for genes. Because nothing lives forever, reproduction is how life sustains itself, and it happens most fundamentally in the division and replication of the cell, known as mitosis. Now new research at Rockefeller University has detailed a key role in mitosis for a chemical modification to histone proteins that package lengthy strings of DNA into compact chromosomes. The experiments, recently published in Science, add to an increasingly intricate picture of the precisely timed events that separate new copies of chromosomes to opposite ends of a cell just before the cell divides, one of the most fundamental processes involved in the reproduction of life.
Modify and divide. New research suggests a chemical modification to the DNA packaging protein site H3T3 (purple) is necessary for the recruitment of the chromosomal passenger complex (green) which helps segregate chromosomes in preparation for cell division. (Credit: Image courtesy of Rockefeller University)
"We've known that histones become decorated during mitosis for more than 30 years, but we haven't really understood their function," says Hironori Funabiki, head of the Laboratory of Chromosome and Cell Biology. "Now we've finally decoded exactly how one of these marks works."
Funabiki says the findings provide hard evidence for the "histone code hypothesis," advanced by Rockefeller's C. David Allis and colleagues, which suggests that combinations of histone modifications attract or remove specific proteins, controlling the immediate environment of chromosomes in the cell. The orchestration of the exact timing and localization of the vast array of molecules and processes involved in reproducing the chromosomes is one of the basic wonders of biology and is at the core of both healthy living and diseases such as cancer, that arise when the process goes awry.
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Published Online August 12, 2010
Science DOI: 10.1126/science.1189505
Survivin Reads Phosphorylated Histone H3 Threonine 3 to Activate the Mitotic Kinase
Aurora BAlexander E. Kelly,1,*, Cristina Ghenoiu,1,2, John Z. Xue,1 Christian Zierhut,1 Hiroshi Kimura,3Hironori Funabiki1,*
Abstract
A hallmark of mitosis is the appearance of high levels of histone phosphorylation, yet the roles of these modifications remain largely unknown. Here, we demonstrate that histone H3 phosphorylated at threonine 3 is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of Survivin, a member of the chromosomal passenger complex (CPC). This binding mediates recruitment of the CPC to chromosomes and resulting activation of its kinase subunit Aurora B. Consistently, modulation of the kinase activity of Haspin, which phosphorylates H3T3, leads to defects in the Aurora B–dependent processes of spindle assembly and inhibition of nuclear re-formation. These findings establish a direct cellular role for mitotic histone H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.
1 Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
2 Weill Cornell Graduate School of Biomedical Sciences, Department of Molecular Biology, Cornell Medical School, New York, NY 10021, USA.
3 School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
These authors contributed equally to this work.
* To whom correspondence should be addressed. E-mail: funabih@rockefeller.edu (H.F.); akelly@rockefeller.edu(A.E.K.)
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