Ricerc@Sapienza

Nuclear envelope ruptures create genome instability and favor cancer invasion. The ESCRT machinery, at first associated with membrane trafficking and cytokinesis, also operates at the nuclear envelope to ensure its integrity. AKTIP (in human, Ft1 in mice) is a factor enriched in foci at the nuclear rim controlling telomere function, genome stability and nuclear envelope integrity. AKTIP is also associated with ESCRTs and structurally similar to the ESCRT factor TSG101. Along with this, Ft1 depletion is a concausal element for aggressive and diffused lymphomas in mice and AKTIP is found altered in human cancer.
These data suggest that the mechanistic explanation for AKTIP/Ft1 in telomere function, genome stability and cancer aggressiveness is linked to its activity at the nuclear envelope, in association with ESCRTs. AKTIP/Ft1 and ESCRT dysfunction would trigger a vicious cycle of fragile nuclei, telomere attrition and genome instability causing the aggressiveness and invasion of lymphomas.
The main aim in this proposal is to investigate and dissect the connection between nuclear integrity and telomere attrition in lymphomagenesis. The first goal is to define the ultrastructural organization and dynamics of AKTIP and ESCRT complexes at the nuclear rim. Secondly, I propose to analyze the impact AKTIP and ESCRTs in telomere function, genetic rearrangements and lymphomagenesis.
I believe that this study will contribute to the characterization of the molecular mechanisms ensuring nuclear envelope integrity implicated in the control of genome stability and telomere function, along with giving insights into their impact on lymphomagenesis.
I wish with this study to give insights into the connections between nuclear envelope and carcinogenesis and to validate new putative cancer players and biomarkers opening the road to the design of novel anticancer strategies, including the use of nuclear envelope
remodeling compounds.