PRBB-CRG Sessions Michael Lisby Department of Biology, University of Copenhagen, Copenhagen DK "TopBP1/Dpb11 ensures faithful sister chromatid segregation in mitosis"
Host: Manuel Mendoza (CRG)
Abstract: DNA anaphase bridges are a potential source of genome instability that may lead to chromosome breakage or non-disjunction during mitosis. Two classes of anaphase bridges can be distinguished: DAPI-positive chromatin bridges and DAPI-negative ultrafine DNA bridges (UFBs). We find that DNA replication and topological stress is the primary source of UFBs, while chromatin bridges is a result of unscheduled homologous recombination. TopBP1/Dpb11 binds to anaphase bridges and plays an dual role in facilitating the separation of sister chromatids linked by UFBs and in suppressing illegitimate recombination leading to accumulation of chromatin bridges. Importantly, the NoCut checkpoint delays progression from anaphase to abscission in yeast cells with anaphase bridges independently of Dpb11, and disruption of the NoCut checkpoint in Dpb11-depleted cells led to a synergistic increase in genome instability. Our current work is focused at determining the spatial organization of DNA repair and checkpoint proteins along anaphase bridges and their interaction with the mitotic spindle as well as elucidating the resolution of DNA anaphase bridges and transmission of damaged structures to the following cell cycle.
PRBB-CRG Sessions Stephen Blacklow Dept.of Cancer Biology, Dana-Farber Cancer Institute & Dept.of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston (MA) US "to be determined"
PRBB-CRG Sessions James Brugarolas Developmental Biology, Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas (TX) US "Towards a molecular genetic and functional classification of renal cancer"
PRBB-CRG Sessions Robert Schneider Functional Genomics & Cancer, Institut de Génétique et de Biologie Moleculaire et Cellulaire (IGBMC), Illkirch FR "Novel Players in Chromatin"
Host: Luciano di Croce (CRG)
Abstract: One of the major goals of post-genomic biological research is to understand the molecular basis and physiological role of covalent protein modifications. These post-translational modifications (PTMs) can regulate protein interactions and/or stability and thus trigger particular downstream responses. The best-characterised substrates for multisite PTMs are currently the histone proteins. Two of each of the four core histones (H3, H4, H2A and H2B) form the nucleosomal core particle around which 147 bp of DNA are wrapped. It has been suggested that PTMs of histones constitute a so-called "histone code". Nonetheless the set of characterised histone modifications is far from complete and many modifications are awaiting identification. PTMs of histones are also clinically very important. Histone modifying enzymes have been found to be rearranged, mutated or deleted in many different types of. In particular the reversible nature of PTMs has led to the emergence of the promising field of epigenetic therapy. One of key questions in the field is if histone PTMs can be causative for processes like transcription or are just by-products, with limited functional relevance. We recently demonstrated a causative function for lysine acetylation on the lateral surface of the histone octamer. We found that acetylations within the core of the nucleosome at positions that are in contact with the DNA are sufficient to stimulate transcription by modulating histone-DNA binding. Our model is that nucleosome function and signaling to the epigenome is directly regulated by specific lateral surface modifications. Furthermore, we identified additional novel PTMs that act as guardian of genome stability by regulating the activity of transposable elements.