Dottorato in GENETICA E BIOLOGIA MOLECOLARE

Titolo della tesi: “Cellular memory proteins” in the epigenetic regulation of the centromere

Centromeres are chromosomal regions crucial for kinetochore assembly that mediate the attachment of chromosomes to spindle microtubules during cell division ensuring faithful chromosome segregation and genome stability. Any dysfunction in mitotic regulators can lead to cell cycle defects and chromosomal instability, feature of human diseases as cancer. Centromeric chromatin is defined by the incorporation of the histone H3 variant CENP-A. CENP-A nucleosomes are interspersed with canonical H3 nucleosomes that contain specific histone modifications creating an epigenetic landscape which is important for centromere identity and CENP-A incorporation. Despite many studies have been conducted to investigate factors involved in centromere regulation and CENP-A deposition, the complete network of players crucial for CENP-A recruitment to the centromeres remains to be clarified. All living organisms are exposed to environmental stress that can alter physiological processes and cause long-term effects on genome integrity. It has emerged that heat shock can lead to genome instability but molecular mechanisms responsible of this alteration are still unknown. In this study I have first investigated the role of Polyhomeotic (PH) and Enhancer of zeste [E(z)], belonging to Polycomb proteins, in chromosome segregation during mitosis. My results indicate that these proteins may be essential for the epigenetic regulation of the centromere and CENP-A deposition. Further, I investigated how heat shock can impact genome integrity and chromosomal stability by focusing on centromere dysfunction and the involvement of Trx-G proteins in this context. Lastly, I have shown that heat shock and genome instability induced by stress can contribute to tumorigenesis and cancer progression employing an in vivo model of cancer in Drosophila.