Penn study reveals structure of cell division's key molecule
Thursday, 23 September 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.
This is a 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.
Ben Black, PhD, assistant professor of Biochemistry and Biophysics, and Nikolina Sekulic, PhD, a postdoctoral fellow in the Black lab, report in the September 16 issue of Nature the structure of the CENP-A molecule, which defines a part of the chromosome called the centromere. Specialized molecules called spindle fibres attach that help pull daughter cells apart during cell division to this constricted area.
"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 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, control part of cell division. 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 fibres attach independently of the underlying DNA sequence. CENP-A has been suspected to be the key epigenetic marker protein.
However, what hasn't been known is how CENP-A epigenetically marks the centromere to direct inheritance. The Black team found the structural features that confer CENP-A the ability to mark centromere location on each chromosome. This is important because without CENP-A or the centromere mark it creates, the entire chromosome — and all of the genes it houses — are lost at cell division.
Structure of the centromere histone complex
containing two chains of CENP-A (red) and
two copies of its close binding partner,
histone H4 (blue). Credit: Ben E. Black,
University of Pennsylvania School of
This CENP-A centromere identifier attracts other proteins, and in cell division builds a massive structure, the kinetochore, for pulling the duplicated chromosomes apart during cell division.
Besides the major advance in the understanding of the molecules driving human inheritance, this work also brings about the exciting prospect that the key epigenetic components are now in hand to engineer clinically useful artificial chromosomes that will be inherited alongside our own natural chromosomes — and with the same high fidelity, says Black.
Source: University of Pennsylvania School of Medicine
Contact: Karen Kreeger
For more on stem cells and cloning, go to CellNEWS at