Cohesin function in chromosome segregation and regulation of gene expression
Co-workers: Mrs Jean Metson, Dr Lana Strmecki, Dr Maurici Brunet Roig, Dr Thomas Gligoris, Dr Johanna Scheinost, Mr Jonathan Godwin, Dr Martin Houlard, Dr Madhusudhan Srinivasan, Dr Sugako Ogushi, Dr Christophe Chapard, Dr Naomi Petela, Mr James Rhodes,
Mr James Collier, Ms Nehir Banaz, Ms Catriona Conway, Mr Menelaos Voulgaris and Mr Antonio Valdés Gutiérrez
One of the most important concepts in biology is that the properties of individual cells are determined by the chromosomes that they inherit. A key observation leading to this notion was that cell division is preceded by the condensation of its chromosomes from interphase chromatin and their subsequent disjunction to opposite poles of the cell prior to its division, a process known as mitosis. We now know that the hereditary material of chromosomes is DNA and that each chromosome contains a single immensely long molecule that is usually replicated many hours before cells actually enter mitosis. What has remained mysterious until recently is what holds sister DNAs together.
Work in our lab has shown that sister chromatids are held together by a multi-subunit complex called cohesin. A protease called separase opens the cohesin ring by cleaving its α kleisin subunit, which causes cohesin’s dissociation from chromosomes and triggers sister chromatid disjunction.
We have proposed that cohesin holds sister DNAs together by trapping them within its ring structure. As predicted by this hypothesis introduction of site-specific chemical cross links at the three interfaces between cohesin’s Smc1, Smc3, and kleisin subunits traps circular sister DNAs inside a single circular cohesin molecule even after protein denaturation.
Our research focuses on the following questions:
Which of cohesin's three interfaces opens to permit DNA entry?
Do its ABC-like ATPases facilitate this process and if so what is the role of the cohesin loading complex?
How do Wapl and Pds5 stimulate the release of cohesin from the DNA?
What function does cohesin have in regulating gene expression during interphase?
Do cohesin and condensin create DNA loops by extrusion of chromatin through their lumens?
To answer these questions our lab applies genetics, biochemistry, structural biology, genome-wide sequencing techniques and advanced microscopy in both mammalian and yeast systems.
- Beckouët, F., Srinivasan, M., Roig, M. B., Chan, K.-L., Scheinost, J. C., Batty, P., Hu, B., Petela, N., Gligoris, T., Smith, A. C., Strmecki, L., Rowland, B. D. & Nasmyth, K. Releasing Activity Disengages Cohesin's Smc3/Scc1 Interface in a Process Blocked by Acetylation. Mol. Cell 61, 563–574 (2016)
- Houlard, M., Godwin, J., Metson, J., Lee, J., Hirano, T. & Nasmyth, K. Condensin confers the longitudinal rigidity of chromosomes. Nat. Cell Biol. 17, 771–781 (2015)
- Gligoris, T. G., Scheinost, J. C., Bürmann, F., Petela, N., Chan, K.-L., Uluocak, P., Beckouët, F., Gruber, S., Nasmyth, K. & Löwe, J. Closing the cohesin ring: structure and function of its Smc3-kleisin interface. Science 346, 963–967 (2014)
Some Older Publications
- Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J. & Nasmyth, K. The cohesin ring concatenates sister DNA molecules. Nature 454, 297–301 (2008).
- Gruber, S., Haering, C. H. & Nasmyth, K. Chromosomal cohesin forms a ring. Cell 112, 765–777 (2003).
- Uhlmann, F., Lottspeich, F. & Nasmyth, K. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400, 37–42 (1999)
- Michaelis, C., Ciosk, R. & Nasmyth, K. Cohesins: chromosomal proteins that prevent premature separation of sister chromatids. Cell 91, 35–45 (1997).
Figure 1: A model of the cohesin complex. Structural work in our group is done in collaboration with Jan Löwe at the LMB in Cambridge, UK.
Figure 2: The cohesin ring entraps sister DNAs. Solving the crystal structures of cohesin’s three interfaces allowed us to chemically circularise the ring. Here we show that sister chromatid cohesion is mediated by entrapment of DNA within a single cohesin ring.
Figure 3: Average cohesin distribution around centromeres in yeast measured by calibrated Chip Sequencing
Figure 5: Trajectories of individual cohesin molecules in human cells. The Scc1 subunit of cohesin was tagged with the HaloTag in U2OS cells and labelled with JF549
Figure 4: Condensin complex shapes meiotic chromosomes in mouse oocytes. Chromosome spreads from mouse oocytes in Meiosis I stained with DAPI.