An unlikely, decadelong journey that began with the discovery of a rapidly aging mouse has led scientists to a protein that seems to protect animals from cancer and other scourges of old age — with no apparent downsides. There are still lots of mysteries about the protein, called BubR1, but the work offers clues about how protecting chromosomes can enhance health.
Cancer biologist Jan van Deursen at the Mayo Clinic in Rochester, Minn., and his colleagues were initially interested in studying a common feature of cancers, called aneuploidy. Aneuploid cells have too few or too many chromosomes. Nearly all cancer cells fall into this category, but it’s not clear whether aneuploidy actually causes cancer. van Deursen, along with a then-graduate student, Darren Baker, engineered mice to produce less BubR1, a protein that helps cells segregate their chromosomes when they divide. When BubR1 is reduced, chromosomes can’t properly separate into identical daughter cells, leaving some cells with the wrong number of chromosomes. Van Deursen, Baker, and their colleagues wanted to see whether these mice would develop cancer.
To their surprise, instead of tumor-filled mice, they wound up with animals that aged very quickly. “These mice were clearly very, very different than a normal mouse," says Baker, who now studies the biology of aging at the Mayo Clinic. Last year, they reported that removing old cells — that is, cells with a genetic marker indicating senescence — from these mice could help them stay healthier longer. Adding intrigue is an extremely rare human condition caused by mutations in the BubR1 gene. Patients with the disease, mosaic variegated aneuploidy syndrome, age prematurely and have an elevated risk of cancer. Too little BubR1 seems to be bad news.
Too much, on the other hand, might be a good thing. In work published recently in Nature Cell Biology, the biologists report that genetically engineered mice that make extra BubR1 are less prone to cancer. For example, they found that when they exposed normal mice to a chemical that causes lung and skin tumors, all of them got cancer. But only 33 percent of those overexpressing BubR1 at high levels did. They also found that these animals developed fatal cancers much later than normal mice.