Our overarching goal is to understand how cells prevent and cope with the occurrence of dicentric chromosomes. The budding yeast Saccharomyces cerevisiae is a great model system for addressing these basic questions through the advanced molecular genetics and cell biology approaches it offers. In particular, it allowed us to develop very sensitive and quantitative assays to detect the formation of dicentrics and monitor dicentric breakage in cells progressing through mitosis.

The first barrier against dicentrics formed by end-to-end chromosome fusion is the inhibition of the non-homologous end joining (NHEJ) repair pathway at telomeres. Proteins bound to the telomeric repeated sequences establish this ubiquitous constitutive cis-inhibition. Its strength and reliability are the result of both the multiplicity of DNA-bound molecules at each telomere and the synergy between several pathways of inhibition (Marcand et al. 2008; Lescasse et al. 2013; Marcand 2014​). One of our aims is to decipher how each individual pathway inhibits NHEJ.​

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​How do dicentrics break?

Dicentric instability is a challenge to their study, explaining perhaps our relative lack of knowledge on how they break during mitosis. In budding yeast, owing to a conditional centromere on one chromosome, conditional dicentrics can be created by telomere fusions or by recombination-induced rearrangements and amplified as stable monocentric chromosomes in conditions that maintain the conditional centromere inactive. This centromere can be reactivated rapidly, allowing the study of dicentric breakage during a single mitosis in homogenous and synchronized populations of cells, each containing the same dicentric (Pobiega and Marcand 2010). With this method, we have identified several contextual elements of the dicentric breakage process (e.g. the positions on chromosomes, the location in the cell and the timing during mitotic exit) (Lopez, Barinova et al. 2015)​. Key questions remain unanswered: we ignore how DNA is broken and what defines the position of breakage. But given our successes so far, we will continue to address them using the combination of approaches offered by this marvellous model system.​