Cell division relies on centromeres, which connect chromosomes to the spindle for separating sister chromatids in mitosis. Human centromeres are composed of large arrays of repetitive DNA, which are often sites of aberrant rearrangements in cancer. While centromere defects can cause chromosomal instability, the molecular mechanisms that maintain their repetitive DNA stable are poorly understood. During the fellowship, I aim to investigate how human centromere stability is maintained and the consequences of centromere dysfunction in driving cancer and aging. To circumvent impeding technical barriers due to incomplete centromere sequence annotation, I have ideated the use of Chromosome Orientation Fluorescence In Situ Hybridization at human centromeres (Cen-CO-FISH; Giunta, 2018). Using this innovative technique, I revealed that CENP-A and CCAN (constitutive centromere-associated network) proteins prevent centromere instability, and this functionality is compromised in cancer cell lines and in primary cells undergoing senescence (Giunta & Funabiki, 2017); my data show that CENP-A may play a new role during centromere replication, preventing DNA damage, repeats shortening, and subsequent aneuploidy. I will use the Auxin-Inducible Degron (AID) system and CRISPR-Cas genome editing with high-throughput imaging of Cen-CO-FISH to identify the human centromere maintenance network and investigate the mechanisms of repeats stability. I will also examine the consequences of centromeres dysfunction, including changes in the size of the array, cell ploidy and proliferation dynamics, using a variety of validated and novel methods, including Cen-qRT-PCR, qFISH and cytogenetic assays. Altogether, the proposed research will unveil a novel conceptual framework to explain the fragility of repetitive centromere DNA and its consequences on cell physiology and disease. This work will lay the foundation for my future independent research on centromere instability in age-associated cancers.
Are you the coordinator (or a participant) of this project? Plaese send me more information about the "CENTROMERE STABILITY" project.
For instance: the website url (it has not provided by EU-opendata yet), the logo, a more detailed description of the project (in plain text as a rtf file or a word file), some pictures (as picture files, not embedded into any word file), twitter account, linkedin page, etc.
Send me an email (fabio@fabiodisconzi.com) and I put them in your project's page as son as possible.
Thanks. And then put a link of this page into your project's website.
The information about "CENTROMERE STABILITY" are provided by the European Opendata Portal: CORDIS opendata.
More projects from the same programme (H2020-EU.1.3.2.)
MITafterVIT (2020)
Unravelling maintenance mechanisms of immune tolerance after termination of venom immunotherapy by means of clonal mast cell diseases
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