The ATPases of cohesin interface with regulators to modulate cohesin-mediated DNA tethering

摘要

The bulk of the genetic material in cells from yeast to humans is organized into chromosomes. These chromosomes must be duplicated and the copies need to be segregated every time cells divide. Cohesin is a protein complex that helps to organize the structure of chromosomes by tethering together two regions of DNA, either within a chromosome or between chromosomes. Problems with cohesin have been linked to cancer and birth defects, but it is not clear how cohesin binds DNA and how it makes a tether between two DNA regions. It is also unclear how cohesin’s activity is coordinated with the series of events that allow cells to divide (known as the cell cycle). Cohesin has two active sites that can break down molecules of ATP. Previous research had suggested that these active sites (called ATPases) controlled cohesin’s activity by regulating whether or not it could bind to DNA. However, ?amdere et al. now reveal that cohesin’s ATPases do not simply provide an ‘on/off switch’ for DNA binding. The experiments, which involved a combination of genetic, cell biology and biochemical techniques in budding yeast, instead revealed that one of cohesin’s ATPases regulates structural rearrangements in cohesin that is already bound to DNA. These structural rearrangements fine-tune the complex’s ability to tether two regions of DNA. Further experiments then revealed that two cohesin regulators (namely Eco1 and Wpl1) altered this ATPase active site to control cohesin’s DNA tethering and DNA binding activities. These findings provide a molecular explanation for how these regulators control cohesin’s activity to make sure that the chromosomes have the correct structure during cell division. The next challenge is to identify the structural changes in cohesin that are triggered by cohesin’s two ATPases and to understand how these structural changes promote DNA binding followed by DNA tethering.