March 05, 2013
Cancer often gets going with chromosome instability. Basically a cell gets a mutation that causes its chromosomes to mutate at a higher rate. Now it and any cells that come from it build mutations faster and faster until they hit on the right combination to make the cell cancerous. An accelerating avalanche of mutations has led to cancer.
There are plenty of obvious candidates for the genes that start these avalanches: genes like those involved in segregating chromosomes and repairing DNA, for example. But there are undoubtedly sleeper genes that no one has really thought of. In a new study out in GENETICS, Minaker and coworkers have used the yeast S. cerevisiae to identify three of these genes — GPN1 (previously named NPA3), GPN2, and GPN3.
A mutation in any one of these genes leads to chromosomal problems. For example, mutations in GPN1 and GPN2 cause defects in sister chromatid cohesion and mutations in GPN3 confer a visible chromosome transmission defect. All of the mutants also show increased sensitivity to hydroxyurea and ultraviolet light, two potent mutagens. And if two of the genes are mutated at once, these defects become more severe. Clearly, mutating GPN1, GPN2, and/or GPN3 leads to an increased risk for even more mutations!
What makes this surprising is what these genes actually do in a cell. They are responsible for getting RNA polymerase II (RNAPII) and RNA polymerase III (RNAPIII) into the nucleus and assembled properly. This was known before for GPN1, but here the authors show that in gpn2 and gpn3 mutants, RNAPII and RNAPIII subunits also fail to get into the nucleus. Genetic and physical interactions between all three GPN proteins suggest that they work together in overlapping ways to get enough RNAPII and RNAPIII chugging away in the nucleus.
So it looks like having too little RNAPII and RNAPIII in the nucleus causes chromosome instability. This is consistent with previous work that shows that mutations in many of the RNAPII subunits have similar effects. Still, these genes would not be the first ones most scientists would look at when trying to find causes of chromosomal instability. Score another point for unbiased screens in yeast leading to a better understanding of human disease.
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics