Successful cell division requires the balanced distribution of chromosomes and cytoplasmic material to daughter cells. In eukaryotes, this is achieved via a series of coordinated cytoskeletal processes which include centrosomes mediated spindle assembly, chromosome segregation, spindle positioning and cytokinesis. In past work, we have found that 12 protein subunits of SRCAP and P400 chromatin remodeling complexes localize to the mitotic apparatus (centrosomes, spindle and midbody) and their depletion disrupt mitosis and cytokinesis in HeLa cells. Overall, these results suggested that, beside their role of epigenetic regulators, chromatin remodeling complexes subunits play previously undetected and evolutionary conserved roles in cell division control.
In this proposal, we will combine cell biology, molecular and biochemical approaches to investigate in more detail the functional roles played by two chromatin remodeling proteins, SRCAP and CFDP1, during cell division in human cells. We will focus our attention on these proteins because they are essential for proper development in vertebrates. The results of the proposed experiments will contribute to gain mechanistic insights into the functions played by SRCAP and CFDP1 as regulator of mitosis and cytokinesis, and into the mechanisms that mediate their recruitment to the mitotic apparatus. Since,mitosis and cytokinesis alterations result in genetic instability, the expected results may also to have an impact on cancer research.
We have shown the existence of previously undetected, massive and evolutionary conserved phenomenon, whereby subunits of SRCAP and P400/TIP60 chromatin remodeling complexes, independently of their roles in chromatin regulation, are massively recruited to the mitotic apparatus and partecipate in the control of spindle and MB functions during mitosis and cytokinesis [9].
Given that the main function of SRCAP and p400/Tip60 complexes is to govern the deposition of the H2A variant histone in animal and plant species, our findings open up new frontiers for the study of cell division.
The results of the present project will contribute to gain mechanistic insights into the functions played by SRCAP and CFDP1 as regulator of cell division and into the mechanisms that mediate their recruitment to the mitotic apparatus. Moreover, since mitosis and cytokinesis failure can lead to genetically unstable states, hence activating tumorigenic transformation, the results of this project are also expected to have a significant impact on cancer research.