Understanding the role of chromatin remodelling in telomere maintenance

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Our chromosomes are long linear pieces of DNA and, just like any thread, the ends of chromosomes (termed telomeres) are fragile and prone to fraying. Telomeres consist of specific DNA sequences and associated binding proteins that protect chromosomes from DNA damage. One of the main factors that affect DNA damage and repair is the chromatin context within which the DNA damage occurs. Chromatin is the native form that all eukaryotic genomes are found as; not as naked DNA but rather as a combination of DNA with proteins that compacts genomic DNA to fit into the nucleus. Chromatin has a profound effect on all processes that require access to genomic DNA. Therefore the cell has developed means of regulating chromatin structure. One of the most important of these is the action of ATP-dependent chromatin remodelling enzymes (Snf2 proteins). These Snf2 enzymes use the energy from ATP hydrolysis to change chromatin structure and thereby alter the accessibility of the underlying DNA.Snf2 proteins are known to regulate DNA repair throughout chromosomes. However, their function at telomeres is much less understood. This is important to address as mutations in some Snf2 proteins are linked to inappropriate DNA repair at telomeres that define a subset of human cancers. Therefore, we need to understand the nature of chromatin remodelling at telomeres and how this affects DNA repair. This is a complex topic and therefore our best chance of understanding the underlying mechanisms lie in studying model organisms with simplified DNA repair and chromatin remodelling pathways. We will use budding yeast, a single-celled eukaryote that for many years has pioneered our understanding of how chromatin affects DNA repair. The budding yeast Snf2 protein Uls1 was recently found to bind telomeres and its deletion results in telomere fusions (a type of inappropriate DNA repair). Our research will address how Uls1 works, what its remodelling and why this affects telomeres. An additional aspect of Uls1 that makes it worthy of study is its connection to SUMO (Small Ubiquitin-like modifier). Cells commonly use the attachment of reversible marks (post-translational modifications) to proteins as molecular switches and SUMO is one such modification. However, in the context of DNA damage, SUMO is particularly important as it regulates DNA repair processes. How Uls1 co-ordinates chromatin remodelling with changes in sumoylation status may reveal novel insight into telomeres and DNA repair. This work will begin to answer fundamental questions about the nature of chromatin remodelling at telomeres: a basic biological problem. It will also lay the foundation for future research into the links between chromatin remodelling, SUMO modification and telomere maintenance that may have translational impact.