Centro Andaluz de Biología Molecular y Medicina Regenerativa
Fernando Romero Balestra

e-mail: fernando.balestra@cabimer.es

Centriole assembly and function in human cells

We are interested in understanding the molecular pathways regulating centriole assembly and centriole number control. Centrosomes are the main microtubule-organizing centers of animal cells. Extremely well conserved across evolution, they are composed of a pair of centrioles surrounded by a cloud of pericentriolar material. Centrioles themselves are microtubule based cylindrical structures, of approximately 500nm length and 200nm wide in humans. Proteomic and bioinformatics analysis have identified hundreds of proteins that localize to the centriole/centrosome, however, the function of the vast majority of these proteins remains a mystery. In addition to their role in organizing the MT cytoskeleton during interphase, the centrosomes/centrioles as MTOCs are also key components of the mitotic spindle. Furthermore in non-dividing cells, the centrioles (known at this stage as basal bodies) are essential for the formation of the primary cilia and flagella. The primary cilia is an organelle present in up to 90% of non-cycling human cells specialized in cell signaling. Overall, centrioles are key players in fundamental cellular processes such as chromosome segregation, spindle orientation, cell migration, cell polarity, cell signaling, sperm formation and lymphocyte T cell synapse.

To efficiently achieve all these functions the cell also needs to bear the right number of centrioles. Remarkably, patient’s cells from many types of cancers have in common the feature of bearing centriole abnormalities or extra number of centrioles, which are either proposed or proved to be at the molecular root of these pathologies. We believe that further understanding the molecular mechanism regulating centriole number homeostasis will contribute to identify pathways and molecular targets to battle cancer. We performed a functional genome-wide screen that identified 76 new potential regulators of centriole assembly or centriole number control (Balestra et al. Dev Cell 2013). The detailed characterization of the molecular function of these candidates in centriole biology is our current focus of research.

Main Research Lines:

  • Centriole assembly: We are characterizing the role of identified proteins involved in the canonical centriole assembly pathway. We are also studding the functionality of partially build centrioles to connect centriole architecture with centriole function.
  • Centriole number control: We are trying to reveal new mechanisms involved in the regulation of the canonical centriole duplication pathway or alternatively restricting centriole assembly by other centriole assembly pathways.
  • Centriole positioning: We have performed a genome-wide analysis to identify regulators of centriole position in human cells. We are focus on those candidates involved in the connection between the centrosomes and the nuclear surface.
  • Centriole and DNA damage response: In collaboration with the DNA double strand break repair and human disease lab headed by Pablo Huertas we are trying to unravel the connection between centrosomes and the DNA damage response.

Gavilan M.P., Gandolfo p., Balestra F. R., Arias F., y Ríos R. M. 2018. The dual role of the centrosome in organizing the microtubule network in interphase. EMBO Rep. 2018 Nov;19(11).

Wolf B, Balestra F. R., Spahr A, Gönczy P. ZYG-1 promotes limited centriole amplification in the C. elegans seam lineage . Developmental Biology. 2018. 434-2, pp.221-230.

Balestra, F. R.; von Tobel, L.; Gönczy, P. Paternally contributed centrioles exhibit exceptional persistence in C. elegans embryos. Cell research. 2015. 25-5, pp.642-646. ISSN 1748-7838.

von Tobel, L.,  Mikeladze-Dvali, T.,  Delattre, M.,  Balestra, F.R.,  Blanchoud, S.,  Finger, S.,  Knott, G.,  Müller-Reichert, T.,  Gönczy, P. SAS-1 is a C2 domain protein critical for centriole integrity in C. elegans. 2014. PLoS genetics. 10-11, pp.e1004777. ISSN 1553-7404.

Balestra, F. R. y Gönczy, P. Multiciliogenesis: multicilin directs transcriptional activation of centriole formation. 2014. Current biology : CB. 24-16, pp.R746. ISSN 1879-0445.

Balestra, F. R., Strnad, P., Flückiger, I. y Gönczy, P. Discovering regulators of centriole biogenesis through siRNA-based functional genomics in human cells. 2013. Developmental cell. 25-6, pp.555-626. ISSN 1878-1551.

Balestra F. R.  and Pierre Gönczy. 2013. Centriole Screen.
Publicación de datos en Applicación web.

Kitagawa, D.,  Kohlmaier, G.,  Keller, D.,  Strnad, P.,  Balestra, F. R.,  Flückiger, I.,  Gönczy, P. Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL. 2011. Journal of cell science. 124-Pt 22, pp.3884-3977. ISSN 1477-9137.

Balestra, F. R. y Jimenez, J. A G2-phase microtubule-damage response in fission yeast. 2008. Genetics. 180-4, pp.2073-2153. ISSN 0016-6731.