Chromosomes responsible for a critical enzyme's activation during cell division

Aug 1 2007

In a dividing cell, chromosomes interact with cellular scaffolding - called spindle microtubules - in order to move themselves to opposite ends of the cell, ensuring that both daughter cells receive an exact copy of their parent cell's genetic material.

The microtubules that form this scaffolding must have impeccable timing. They materialize only in the presence of the migrating chromosomes and dissipate as soon as they're no longer needed. New research from Rockefeller University suggests that an enzyme, called Aurora B, is the reason they show up on time.

Cell division is among the most fundamental processes of biology, and if something goes wrong at any point during the meticulously orchestrated process, the mistake could result in the misdistribution of chromosomes and lead to cancer or other diseases. So researchers are concentrating on every step of the process, trying to learn as much as they can about how cells divide and which molecules are involved. Assistant Professor Hironori Funabiki, head of the Laboratory of Chromosome and Cell Biology, is particularly interested in how chromosomes are responsible for directing cell division and in how microtubules form the bipolar spindle. The latter is the critical step that allows the chromosomes to align, and involves at least three cellular pathways , one of which, the ,chromosomal passenger complex, or CPC, Funabiki recently discovered.

The CPC is a group of proteins that bind to chromosomes as they're lined up along the cell's center in preparation for division. The new research from Funabiki, Alex Kelly, a postdoctoral fellow in his lab, and their colleagues shows that the ability of the bipolar spindle to assemble only in the presence of chromosomal DNA can be pinned on a specific enzyme in the CPC, the Aurora B kinase.

Kelly and Funabiki found that spindle formation requires multiple molecules of Aurora B, and that the presence of chromosomes greatly increases the probability that numerous molecules will be found in one place. In order for the kinase to be fully activated, a protein called Incenp must bind to and receive a phosphate group. But once the two molecules are bound, their conformation leaves them too far away from each other to completely transfer the phosphate group and they have to bring another Aurora B molecule in for total activation. In research reported in Developmental Cell , Funabiki and Kelly show that, because a cell's chromosomal DNA has many sites at which the CPC can attach, the presence of chromosomes therefore increases the frequency with which Aurora B molecules can collide.

The increased density of docking sites for CPC molecules, and thus increased density of Aurora B and Incenp, means that cells can only make spindles in the presence of chromosomes. "When you decouple the link between chromosomes and Aurora B," Kelly says, "the system no longer makes spindles only around chromosomes. You get spindles forming elsewhere, without DNA in the middle."