The Chromosome That Got Away

Mathematically, tumors should not exist: In theory, cells do not mutate fast enough to overcome the genetic checks and balances that prevent damaged cells from reproducing out of control. Now, researchers may have an answer to this paradox for some cancers: A single mutation can shut off the "stop" signal that normally prevents defective cells from dividing. As a result, cells may end up with too few chromosomes, which could cause the loss of key tumor-suppressing genes.

A key moment during cell division--or mitosis--is the separation of DNA, so that each daughter cell inherits a full complement of genes. The duplicated chromosomes--consisting of a pair of identical chromatids--attach themselves to a spindle of tubular proteins. The chromosomes are then pulled apart and one chromatid is dragged to each end of the cell. To prevent being left behind in only one daughter cell, any chromosome that hasn't caught onto the spindle releases a signal to prevent cell division. So far, six genes involved in this emergency brake have been found in yeast.

To check on whether these genes contribute to human cancer, the researchers--from Johns Hopkins School of Medicine in Baltimore and Case Western Reserve University in Cleveland--focused on a yeast gene, called BUB1, that has a human equivalent, hBUB1. They then searched for hBUB1 mutations in cancerous colorectal cells. After finding two mutations, they inserted these mutant alleles into cells with a normal number of chromosomes. This disrupted the control of mitosis, the researchers report in this week's issue of Nature. "Only one defective copy is necessary to poison the process of monitoring chromosome stability," adds Daniel Cahill of Johns Hopkins.

The findings about hBUB1 show how important regulatory genes are to squelching tumors, says Terry Orr-Weaver, a geneticist at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. But hBUB1 isn't the whole story: At least two more BUB genes are involved in putting the brakes on cell division, as well as three genes called MAD and one called MPS, she says. The new research suggests that disrupting any component of that system might lead to defective chromosomes and to cancer.