Phd in GENETICS AND MOLECULAR BIOLOGY

Thesis title: Non-canonical role of chromatin remodelling complexes: lessons from SRCAP ATPase

Chromatin is a highly dynamic nucleoprotein structure which organization is finely regulated to ensure the balance between packaging and accessibility of the eukaryotic genome. Such regulation is mainly mediated by covalent histone modifiers and chromatin remodeling complexes (CRCs). Four families of ATP-dependent CRCs are currently known (INO80, SWI/SNF, ISWI, CHD). Among them the human INO80 family includes the SRCAP and Tip60/p400 complexes. The main function of these two complexes is to promote the exchange of the canonical histone H2A with the histone H2A variants (H2A.X, H2A.Z). The results of two recently papers, published by our group, support the existence of an evolutionarily conserved phenomenon in which the subunits of SRCAP and Tip60/p400 complexes relocate from chromatin to mitotic apparatus, playing a role in human and Drosophila cell division. In this context, my PhD project is aimed to deepen our understanding of the extra-chromatin roles played by the SRCAP subunit and to get mechanistic insight on the molecular aspects of this multi-functional ATPase and on its interaction network during mitosis and cytokinesis. Moreover, because Srcap gene dominant mutations are known to cause the Floating-Harbor developmental syndrome (FHS), it was also analysed the progression of cell division in one lymphoblastoid cell line derived from a FHS patient. The results of my work suggested that SRCAP may be involved in: i) promoting mitotic spindle dynamics by ensuring microtubules polymerization and/or stabilization, as a new microtubule associated protein (MAP), and ii) contributing to secure the final cut necessary for proper execution of abscission during cytokinesis. Finally, these results suggested that, in addition to the chromatin regulation defects, a misfunctional SRCAP ATPase causes cell division defects that contribute to the onset of the developmental abnormalities characteristic of FHS.