Conformational dynamics of cohesin/Scc2 loading complex are regulated by Smc3 acetylation and ATP binding

The ring-shaped cohesin complex is a key player in sister chromatid cohesion, DNA repair, and gene transcription. The loading of cohesin to chromosomes requires the loader Scc2 and is regulated by ATP. This process is hindered by Smc3 acetylation. However, the molecular mechanism underlying this inhibition remains mysterious. Here, using Saccharomyces cerevisiae as a model system, we identify a novel configuration of Scc2 with pre-engaged cohesin and reveal dynamic conformations of the cohesin/Scc2 complex in the loading reaction. We demonstrate that Smc3 acetylation blocks the association of Scc2 with pre-engaged cohesin by impairing the interaction of Scc2 with Smc3's head. Lastly, we show that ATP binding induces the cohesin/Scc2 complex to clamp DNA by promoting the interaction between Scc2 and Smc3 coiled coil. Our results illuminate a dynamic reconfiguration of the cohesin/Scc2 complex during loading and indicate how Smc3 acetylation and ATP regulate this process. Cohesin loading on DNA is a highly dynamic process. Here the authors find that Smc3 acetylation blocks the reconfiguration of the Scc2/cohesin complex by preventing Scc2 from interacting with Smc3, and that ATP binding regulates the DNA clamping step by promoting the Scc2/Smc3 coiled-coil interaction.