Prof Kim Nasmyth
Prof Kim Nasmyth
SMC complex function in chromosome condensation, segregation and regulation of gene expression
Accurate chromosome segregation is an essential aspect of cell proliferation. This remarkable feat is only possible because monumental topological problems posed by the sheer size and physical properties of DNA are overcome by highly conserved DNA motors, namely condensin and cohesin. Replicated DNA is weaved into discrete chromatids during mitosis by condensin, while sister chromatids are held together by cohesin, which is essential for their bi-orientation on mitotic spindles.
Condensin has the remarkable ability to form and expand in a processive manner DNA loops in vitro, an activity known as loop extrusion (LE) which could explain how condensin transforms interphase chromosomes into thread-like chromatids while at the same time accumulating along their longitudinal axis. Cohesin has more diverse activities. In addition to its canonical role of holding together sister chromatids, cohesin also organizes interphase chromatin into defined territories called TADs (Topologically Associated Domains), a process also thought to be driven by LE.
Work in our lab has shown that Cohesin mediates cohesion by entrapping sister DNAs inside its tripartite ring. We have also shown that Cohesin can associate with the DNA either by entrapping individual DNAs or even without any topological entrapment. The nature of cohesin’s association with the DNA during LE is not known. Our research is focused on broadly two key aspects of chromosome segregation:
- Understanding the molecular mechanism of loop extrusion by SMC-Kleisin complexes.
- Understanding the mechanism by which co-entrapment of sister DNAs within the cohesin ring is achieved. To answer these questions our lab applies genetics, biochemistry, structural biology, genome-wide sequencing techniques and advanced microscopy in both mammalian and yeast systems.