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Chromatin Dynamics and Chromosome Architecture

Chromatin Dynamics and Chromosome Architecture - P. BERNARD

The main goal of our research is to understand the mechanisms used by cells to assemble mitotic chromosomes that can be efficiently transmitted throughout cell divisions. We use the fission yeast Schizosaccharomyces pombe as a model organism.

Mitotic chromosome assembly is the large scale reorganisation of long and intertwined chromatin fibres into highly compact and highly organised mitotic chromosomes. This metamorphosis of chromatin into chromosomes is an absolute prerequisite for the accurate transmission of genomic DNA during cell division. Failure in chromosome assembly/condensation and/or segregation can irreversibly alter the genome and is considered as a driving force in carcinogenesis.

A key player in the assembly of mitotic chromosomes is the Condensin complex. It is a large proteinaceous ring made of two SMC (Structural Maintenance of Chromosome) ATPases associated with three regulatory subunits. Studies performed in a wide range of organisms have shown that Condensin binding to chromatin and chromosome condensation are mechanistically linked. Yet, how Condensin associates with chromatin in a cell-cycle-regulated manner and, in this context, shapes mitotic chromosomes remain poorly understood.

Condensin possesses an ATP-dependent DNA supercoiling activity that is thought to contribute to chromosome condensation. Condensin also possesses the ability to encircle chromosomal DNA, and this topological mode of association appears instrumental for mitotic chromosome condensation. One model proposes that Condensin shapes chromosomes by creating and/or stabilising intrachromosomal links and chromatin loops.

How does chromosomal DNA enter into the Condensin ring ? How are chromosomal Condensin binding sites defined ? How are Condensin’s association and chromosome condensation reversed upon mitotic exit ? How does Condensin distinguish sister-DNA molecules from homologous chromosomes ? What is the contribution, if any, of chromatin constituents and modifiers in Condensin-mediated chromosome condensation ?

To try and address these fundamental questions we sought to identify cellular factors that collaborate with Condensin through genetic screens. Our main objective now is to characterise these molecules with respect to the association of Condensin with chromatin, mitotic chromosome condensation and segregation by using a combination of molecular biology, genomic, biochemistry and microscopic approaches.