Centrosome defects in neurodevelopment disorders

Mitotic cells are susceptible to genomic alterations through the breakage or mis-segregation of chromosomes. Cells reduce the risk of these defects by carefully monitoring DNA integrity and chromosome attachments with quality-control checkpoints. Our recent identification of a signaling pathway that prevents proliferation following centrosome loss raised the question of how this pathway operates to preserve the integrity of mitosis. To address this question, we designed and executed a pooled genome-wide CRISPR-Cas9 screen to discover essential regulators of the cell cycle arrest caused by centrosome loss. This screen led to the identification of components of a new mitotic fail-safe, known as the mitotic surveillance pathway, which prevents the growth of cells in response to a prolonged mitosis. Importantly, centrosome loss activates this pathway by delaying spindle assembly and mitotic progression. We propose that an increased mitotic duration is recognized as a signal for the elimination of unfit cells that possess unresolved damage. Moreover, our recent work in this area shows that pathological activation of the mitotic surveillance pathway underlies the reduced brain growth in primary microcephaly, a neurodevelopmental disorder caused by mutations that affect centrosome function.

 

Selected papers

p53 protects against genome instability following centriole duplication failure.

Lambrus, B.G., Clutario, K.M., Daggubati, V., Snyder, M., Holland, A.J. Journal of Cell Biology. 2015. 210:63-77. 

 

A USP28-53BP1-p53-p21 signaling axis arrests growth following centrosome loss or prolonged mitosis.

Lambrus, B.G., Daggubati, V., Uetake, Y., Scott, P.M., Clutario, K.M., Sluder, G., Holland, A.J. Journal of Cell Biology. 2016. 214:143-153.

 

Centrosome defects cause microcephaly by activating the mitotic surveillance pathway.

Phan, T., Maryniak, A., Boatwright, C.A., Lee, J., Atkins, A., Tijhuis, A., Spierings, D.C.J., Bazzi, H., Foijer, F., Jordan, P.W., Stracker, T.H., Holland, A.J. Submitted.