Camilla Sjögren, PhD, Professor, Vice-Chairman
The SMC complexes, chromosome dynamics and stability
The molecular mechanisms which maintain genome stability are essential for life and prevent accumulation of disease-promoting chromosomal aberrations. With the aim to decipher these mechanisms, our project focuses on the evolutionary conserved family of SMC protein complexes (SMC: Structural Maintenance of Chromosomes). There are three eukaryotic complexes: cohesin, condensin and the Smc5/6 complex. The majority of our ongoing investigations aim to disclose the function of the Smc5/6 complex, which is the least well understood. We do this using the budding yeast Saccharomyces cerevisiae as model organism.
The Smc5/6 complex has mainly been functionally connected with DNA repair and we have found that it is recruited to DNA breaks where it activates cohesin. We have also shown that Smc5/6 binds to chromosomes as a consequence of DNA replication. Intriguingly, the frequency of Smc5/6 binding sites increases in linear correlation with the length of chromosomes, and we have unraveled a function for Smc5/6 in the resolution of replication-induced topological tension. This tension arises when the replication machinery pries apart the parental double-helix into single DNA strands. If the tension is not removed, it will lead to replication fork blockage which increases the risk of genomic rearrangements. Our more recent results suggest that topological tension also could have a positive role in the organization of chromosomes, executed via the SMC complexes.
Our ongoing and future investigations are based on these findings, and the main objectives are to:
- Establish the molecular details of how the Smc5/6 complex removes topological tension and protects genome stability.
- Characterize the interplay between DNA topology and chromosomes structure, stability and dynamics.
- Takaharu Kanno, Postdoc
- Sidney Carter Dewey, Postdoc
- Kristian Carlborg, PhD-student
- Ingrid Lilienthal, PhD-student
- Kristian Jeppsson, PhD-student
- Davide Berta, PhD-student
The SMC complexes, DNA and chromosome topology - right or knot?
Crit. Rev. Biochem. Mol. Biol. 2012: 47:1-16.
Chromosome length influences replication-induced topological stress.
Nature, 2011; 471; 392-396.
Post-replicative formation of cohesion is required for repair and induced by a single DNA break.
Science, 2007; 317; 242-245.
Chromosomal association of the Smc5/6 complex reveals that it functions in differently regulated pathways.
Mol. Cell, 2006; 22; 755- 767.
Postreplicative recruitment of Cohesin to double-strand breaks is required for DNA repair.
Mol. Cell, 2004; 16; 1003-1015.