Molecular control of centrosome copy number

Centrioles are microtubule-based structures that recruit a surrounding pericentriolar material to form the centrosome. Centrosomes nucleate the assembly of the microtubule cytoskeleton in interphase cells and form the poles of the mitotic spindle during cell division. Centriole duplication occurs once per cell cycle and is controlled by the conserved master regulator Polo-like kinase 4 (PLK4). Abnormal expression of PLK4 has been linked with tumorigenesis and drugs targeting PLK4 have recently entered clinical trials. Although significant progress has been made in understanding centriole composition, we do not understand how PLK4 activity controls specific steps in centriole formation. We showed that PLK4 kinase activity is controlled by binding to a protein called STIL that is found in the central part of the centriole. In addition, PLK4 phosphorylates its substrate STIL in two conserved regions to promote distinct binding interactions that together scaffold new centriole assembly. This provides a conceptual framework for understanding the control of centriole biogenesis and how this process can go awry in human tumors. Working with Andrew Goryachev’s lab, we incorporated what we learned from our studies on PLK4 to develop a mechanistic biophysical model for the initiation of centriole duplication.

 

Selected papers

Binding to Plk4 activated kinase activity to promote centriole duplication. 

Moyer TC, Clutario KM, Lambrus BG, Daggubati V, Holland AJ. Journal of Cell Biology. 2015. Jun 22;209(6):863-78. 

 

Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network.

Leda M, Holland AJ, Goryachev AB. iScience. 2018. Oct 11;8: 222-35. 

 

Once and only once: mechanisms of centriole duplication and their deregulation in disease.

Nigg, E.A., Holland, A.J. Nature Reviews Molecular Cell Biology. 2018. 19(5): 297-312.

 

PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole to the microtubule wall.

Moyer, T.C. and Holland, A.J. eLIFE. 2019 8: e46054.

 

Mechanism and regulation of centriole and cilium biogenesis.

Breslow, D.K. and Holland, A.J. Ann Rev Biochem2019 88: 691-724.

 

WBP11 enables centriole biogenesis by mediating the splicing of TUBGCP6 pre-mRNA.

Park E, Scott PM, Clutario KM, Anglen T, Cassidy KB, Gerber SA, Holland AJ. Journal of Cell Biology. 2020. Jan 6;219.