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.
In this proposal, I will study mechanisms of lymphomagenesis analyzing two cancer drivers, telomere dysfunction and NE fragility. Up-to-date cancer science has highlighted their role in tumorigenesis, but has neither investigated them exhaustively nor as interrelated events. Starting from the characterization of AKTIP/Ft1, a new factor impacting on NE properties, telomere function and cancer aggressiveness, I¿m confident that I will give insights into the connections between telomeres, NE, and cancer invasion, along with validating AKTIP/Ft1 as a new putative player in human cancer. Proposed experimental plan focuses on lymphomagenesis because preliminary data on lymphomas are available and also to give a defined picture on a single cancer type. However, the elements chosen in this study represent models for larger interpretation schemes of mechanisms of tumorigenesis, and the study of ESCRT association with tumorigenesis opens the path to the inclusion of these factors as biomarkers of cancer aggressiveness. Along with giving new elements into the pathomolecular players in lymphomagenesis this project wants to explore NE reshaping as an approach to control lymphomagenesis. Experimental medicine based on the manipulation of the mechanical properties of the nuclear membrane in relation with cancer is at its infancy, which obliges to prudence in predicting success. This notwithstanding, addressing NE mechanopathology is a novel and promising area for searching new cancer drugs.
Moreover, this approach can benefit of previous results obtained with compounds being tested for diseases affecting nuclear fragility as premature aging syndromes linked to mutation in NE components.
References of the entire project
1. Schellhaus AK, et al. Nuclear Reformation at the End of Mitosis. J Mol Biol. 2015
2. Crabbe L, et al. Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly. Cell Rep. 2012
3. Spann TP, et al. Disruption of nuclear lamin organization alters the distribution of replication factors and inhibits DNA synthesis. J Cell Biol. 1997
4. Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis. 2010
5. Maciejowski J, et al. Chromothripsis and Kataegis Induced by Telomere Crisis. Cell. 2015
6. Burke B, Stewart CL. Functional architecture of the cell's nucleus in development, aging, and disease. Curr Top Dev Biol. 2014
7. Raab M, et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science. 2016
8. Denais CM, et al. Nuclear envelope rupture and repair during cancer cell migration. Science. 2016
9. Merigliano C, Burla R, Human AKTIP interacts with ESCRT proteins and functions at the midbody in cytokinesis 2020, BioRxiv
10. Burla R, et al. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance. PLoS Genet. 2015
11. Burla R, Carcuro M, Torre ML, Fratini F, Crescenzi M, D'Apice MR, et al. The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence. Open Biol. 2016
12. Burla R, et al. Mammalian telomeres and their partnership with lamins. Nucleus. 2016
13. Morita E, et al. Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J. 2007
14. Xu L, et al. An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex. Mol Biol Cell. 2008
15. Olmos Y, et al. ESCRT-III controls nuclear envelope reformation. Nature. 2015
16. La Torre M, et al. Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits. Aging Cell. 2018
17. Chojnowski A, et al. Progerin reduces LAP2alpha-telomere association in Hutchinson-Gilford progeria. Elife. 2015
18. Pornillos O, et al. Structure and functional interactions of the Tsg101 UEV domain. EMBO J. 2002
19. Burla R, La Torre M, et al. p53-Sensitive Epileptic Behavior and Inflammation in Ft1 Hypomorphic Mice. Front Genet. 2018