Project description
hSpindly as a regulator of the spindle assembly checkpoint system
The eukaryotic spindle assembly checkpoint (SAC) system monitors microtubule attachment to kinetochores, preventing separation of the sister chromatids during mitosis until all the chromosomes are correctly attached to the spindle microtubules and aligned on the metaphase plate. Recently, the new protein Spindly was identified as a specific regulator involved in the stable kinetochore-microtubule interactions and progression into anaphase. The EU-funded SpinSAC project will study mechanisms of function of human Spindly (hSpindly) in SAC regulation. hSpindly is highly phosphorylated in mitosis, and identification of the phosphorylated residues will help clarify its role in the cell response to antimitotic drugs. This knowledge of the hSpindly function could lead to the identification of new therapeutic targets for the treatment of tumours resistant to antimitotic drugs.
Objective
During mitosis a sophisticated surveillance system, known as the spindle assembly checkpoint (SAC), is crucial to make sure that the cell does not separate its sister chromatids until all the chromosomes are correctly attached to spindle microtubules and bi-oriented.
Nowadays, one of the more important strategy used for the cancer treatment is the inhibition of the microtubule dynamic to activate the SAC by the addition of anti-mitotic drugs. At the end, the activation of SAC for a long period provokes the cell death, compromising the tumour cell proliferation. Nonetheless, there are tumour cells, which are affected in SAC activity showing a reduction in the efficiency of this treatment. For this reason, it is becoming extremely useful to seek new proteins which are implicated directly to SAC functionality.
This project will be focused on the study of hSpindly as a new protein implicated in SAC regulation independently of the stripping pathway. hSpindly has a role in the SAC mechanism but how it works is absolutely unknown. hSpindly is highly phosphorylated in mitosis so, finding the residues which are phosphorylated in this cell cycle phase, will allow us to know not only the role of these phosphorylations in SAC but also its implication in the cell response in the presence of antimitotic drugs. For this, we will use several approaches and state of the art techniques as confocal microscopy and the CRISPR/Cas9 nickase system. This study will contribute with relevant results in basic and clinical research. The knowledge of the hSpindly function might reveal new therapeutic targets for the treatment of the tumours more resistant to anti-mitotic drugs. Additionally, it would be possible to get phosphospecific antibodies of key residues in the hSpindly function, which could be used as tumour marker in the future.
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Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
41004 Sevilla
Spain