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Mechanisms that prevent aneuploidy

Objective

The mechanisms that safeguard cells against aneuploidy are of great interest as aneuploidy contributes to tumorigenesis. To gain insight into these mechanisms, I studied the behavior of cells entering mitosis with damaged chromosomes. I used the endonuclease I-CreI to generate acentric chromosomes in Drosophila larvae. While I-CreI expression produces acentric chromosomes in the majority of dividing cells, remarkably, it has no effect on adult survival. Live studies reveal that acentric chromatids segregate efficiently to opposite poles. The acentric chromatid poleward movement is mediated through DNA tethers that connect the acentric fragment to its centric partner. Three highly conserved kinases, BubR1, Aurora B and Polo localize on the tether and facilitates the accurate segregation of acentric chromatids by maintaining the integrity of the tether.
Chromosome segregation must be tightly coordinated with cell division to ensure that cells do not divide before the chromosomes have cleared the cleavage plane. However, the mechanism that permits this coordination is unknown. To identify this mechanism, I studied the behavior of cells going through mitosis with abnormally long chromatids. I took advantage of my previous discovery that acentric chromosomes remain attached to their centric partners by a DNA tether. This tether effectively increases the size of sister chromatids during anaphase. Remarkably, the cell adapts to the size of the long chromatids by increasing in length. Cell elongation enables long chromatids to clear the cleavage plane in time for cell division to occur properly. This novel cell elongation mechanism involves myosin activity.
I have discovered two mechanisms that prevent aneuploidy: the tether-based acentric segregation and the elongation of the cell that clears chromatids from the cleavage plane. Since both are new processes, our understanding of the underlying mechanisms is limited. My proposal aims to decipher these mechanisms.

Call for proposal

ERC-2012-StG_20111109
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Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Address
Rue Michel Ange 3
75794 Paris
France
Activity type
Research Organisations
EU contribution
€ 1 500 000
Principal investigator
Anne Royou (Dr.)
Administrative Contact
Gaëlle Bujan (Ms.)

Beneficiaries (1)

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France
EU contribution
€ 1 500 000
Address
Rue Michel Ange 3
75794 Paris
Activity type
Research Organisations
Principal investigator
Anne Royou (Dr.)
Administrative Contact
Gaëlle Bujan (Ms.)