Telomeres and Chromatin
The first focus of the lab is to understand in budding and fission yeasts the mechanisms of telomere maintenance and the cellular responses to telomere erosion. Our second focus is to investigate the structure and functions of the H3K4 methyltransferase Set1-Complex (COMPASS).
Content and impact of the major scientific contributions:
In the Set1 field
- We showed that the yeast SET domain protein Set1 regulates telomere length and telomeric silencing. We contribute to the notion that DNA damage checkpoint proteins regulate telomere length (Corda et al. Nat Genet 1999) (highlighted in Nat Genet by T. Weinert & V. Lundblad).
- We showed that the histone H3K4 methyl transférase Set1 regulates DNA repair and discover a pathway in response to Set1 dysfunction involving the signalling kinase Rad53 but independent of the Mec1 DNA damage checkpoint protein that targets Replication protein A (Schramke et al. Genes and Dev 2001, Kanoh et al. J Mol Biol 2005)
- We characterize the organisation of the Set1 complex and determine the roles of its subunits in the regulation of histone 3 lysine 4 methylation (Dehe et al. J Biol Chem 2006, Trésaugues et al. 2006 J Mol Biol 2006).
- We contribute to the understanding of the crosstalk between H2B ubiquitylation and H3K4 trimethylation on chromatin (Dehe et al. J Mol Biol 2005).
- We found that the histone H3K4 methyl transférase Set1 is required for meiotic replication and double-strand break formation during meiotic recombination (Sollier et al. EMBO J 2004).
- In collaboration with the group of Alain Nicolas, we pursued this study and demonstrated that histone H3 lysine 4 trimethylation marks meiotic recombination initiation sites (EMBO J, 2009) (highlighted in EMBO J by R.Kniewel and S. Keeney).
- Very recently, we show that the PHD domain protein Spp1 is the key factor that links COMPASS activity to DSB sites. (Acquaviva et al., Submitted)
In the telomere field
- We showed that the single-stranded DNA-binding protein involved in DNA replication, recombination and repair regulates telomerase action by facilitates the action of telomerase at chromosome ends (Schramke, Luciano et al. Nature Genetics, 2004) (Luciano et al., EMBO J, 2012).
- We recently showed that in S. cerevisiae telomerase can be recruited on the lagging and the leading telomere but that the Mre11-Rad50-Xrs2-dependent resection activity is only required for the telomerase recruitment at the leading telomere. (Faure, Coulon et al. Mol Cell 2010) (highlighted in Mol Cell by JM Dewar and D. Lydall).
- In collaboration with the groups of Eric Gilson and Michael Lisby, we did pioneering work to characterize by single cell analysis the telomeric DNA damage response at eroded telomeres. This work reveals that eroded telomeres are recognized by the DNA damage machinery many generations before the onset of replicative senescence and that a single eroded telomere is sufficient to elicit a DNA damage response. Moreover, we found that eroded telomeres relocate from their membrane anchor site to the Nuclear pore complex (Khadaroo et al. Nat Cell Biol, 2009).
- In a related study, we showed that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence (Abdalah, Luciano et al. 2009 Nat Cell Biol, 2009).
In addition to the above contributions, we have been associated as a collaborator to several important studies:
- The first one carried out in Catherine Dargemont laboratory shows that ubiquitylation of the Set1-complex component Swd2 links H2B ubiquitylation to H3K4 trimethylation (Vitalino-Prunier et al. Nat Cell Biol 2009).
- The second work performed in B. Dichtl laboratory reports the co-translational assembly of the yeast SET1C histone methyltransferase complex. To the best of my knowledge, this work delineates for the first time the assembly pathway of a multi-protein complex that is initiated during translation in the cytosol. (Halbach et al. EMBO J 2009).
- The third work was performed in collaboration with the group of Sebastian Chavez, we recently described a new cell cycle surveillance mechanism that allows cells to respond to free histone excess before starting DNA replication (Morillo-Hueca et al. Plos Genetics, 2010).