At the Crossroads of Chromosomes: Study Reveals Structure of Cell Division’s Key Molecule
ScienceDaily (Sep. 17, 2010) — On average, one hundred billion cells in the human body divide over the course of a day. Most of the time the body gets it right but sometimes, problems in cell replication can lead to abnormalities in chromosomes resulting in many types of disorders, from cancer to Down Syndrome.
Human chromosome, with conventional nucleosomes containing the major form of the histones (green), and localization of the centromere histone H3 variant, CENP-A (red). (Credit: Ben E. Black, University of Pennsylvania School of Medicine)
Now, researchers at the University of Pennsylvania's School of Medicine have defined the structure of a key molecule that plays a central role in how DNA is duplicated and then moved correctly and equally into two daughter cells to produce two exact copies of the mother cell. Without this molecule, entire chromosomes could be lost during cell division.
Ben Black, PhD, assistant professor of Biochemistry and Biophysics, and Nikolina Sekulic, PhD, a postdoctoral fellow in the Black lab, report in the Sept. 16 issue of Naturethe structure of the CENP-A molecule, which defines a part of the chromosome called the centromere. This is a constricted area to which specialized molecules called spindle fibers attach that help pull daughter cells apart during cell division.
"Our work gives us the first high-resolution view of the molecules that control genetic inheritance at cell division," says Black. "This is a big step forward in a puzzle that biologists have been chipping away at for over 150 years."
Investigators have known for the last 15 years that part of cell division is controlled by epigenetic processes, the series of actions that affect the protein spools around which DNA is tightly bound, rather than encoded in the DNA sequence itself. Those spools are built of histone proteins, and chemical changes to these spool proteins can either loosen or tighten their interaction with DNA. Epigenetics alter the readout of the genetic code, in some cases ramping a gene's expression up or down. In the case of the centromere, it marks the site where spindle fibers attach independently of the underlying DNA sequence. CENP-A has been suspected to be the key epigenetic marker protein.
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Nature 467, 347-351 (16 September 2010) | doi:10.1038/nature09323; Received 22 February 2010; Accepted 6 July 2010; Published online 25 August 2010
The structure of (CENP-A–H4)2 reveals physical features that mark centromeres
Nikolina Sekulic1, Emily A. Bassett1,2, Danielle J. Rogers1 & Ben E. Black1,2
Department of Biochemistry and Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA
Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA
Correspondence to: Ben E. Black1,2Email: blackbe@mail.med.upenn.edu
Centromeres are specified epigenetically, and the histone H3 variant CENP-A is assembled into the chromatin of all active centromeres1. Divergence from H3 raises the possibility that CENP-A generates unique chromatin features to mark physically centromere location. Here we report the crystal structure of a subnucleosomal heterotetramer, human (CENP-A–H4)2, that reveals three distinguishing properties encoded by the residues that comprise the CENP-A targeting domain (CATD; ref. 2): (1) a CENP-A–CENP-A interface that is substantially rotated relative to the H3–H3 interface; (2) a protruding loop L1 of the opposite charge as that on H3; and (3) strong hydrophobic contacts that rigidify the CENP-A–H4 interface. Residues involved in the CENP-A–CENP-A rotation are required for efficient incorporation into centromeric chromatin, indicating specificity for an unconventional nucleosome shape. DNA topological analysis indicates that CENP-A-containing nucleosomes are octameric with conventional left-handed DNA wrapping, in contrast to other recent proposals3, 4, 5,6. Our results indicate that CENP-A marks centromere location by restructuring the nucleosome from within its folded histone core.
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