The centrosome duplication cycle in health and disease

Abstract

a b s t r a c tCentrioles function in the assembly of centrosomes and cilia. Structural and numerical centrosome aberrations have long been implicated in cancer, and more recent genetic evidence directly links centrosomal proteins to the etiology of ciliopathies, dwarfism and microcephaly. To better understand these disease connections, it will be important to elucidate the biogenesis of centrioles as well as the controls that govern centriole duplication during the cell cycle. Moreover, it remains to be fully understood how these organelles organize a variety of dynamic microtubule-based structures in response to different physiological conditions. In proliferating cells, centrosomes are crucial for the assembly of microtubule arrays, including mitotic spindles, whereas in quiescent cells centrioles function as basal bodies in the formation of ciliary axonemes. In this short review, we briefly introduce the key gene products required for centriole duplication. Then we discuss recent findings on the centriole duplication factor STIL that point to centrosome amplification as a potential root cause for primary microcephaly in humans. We also present recent data on the role of a disease-related centriole-associated protein complex, Cep164-TTBK2, in ciliogenesis.

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…Mutations in centrosomal genes are often connected to developmental malformations of the brain, such as autosomal recessive primary microcephaly, microcephalic osteodysplastic primordial dwarfism type II, and Seckel syndrome, in humans (Nigg, Čajánek, & Arquint, 2014). These rare human diseases have not been studied in the context of AD, in part because they are rare yet patients do not survive long, and because mental retardation symptom is difficult to distinguish from cognitive dysfunction of AD.…”

Centrosome amplification: a suspect in breast cancer and racial disparities

“…Because abnormal centrosome numbers correlate with ploidy in breast cancer, cell doubling events are a likely cause of numerical CA in breast cancer, which has been estimated as explaining at least 15% of CA (i.e., 15% of cells with ploidy >3 have CA, although because chromosomes may subsequently be lost, this statistic may underrepresent the true prevalence of CA caused by doubling events) (Denu et al 2016). The molecules and pathways responsible for numerical CA have been comprehensively reviewed elsewhere (Anderhub, et al 2012; Brownlee and Rogers 2013; Godinho and Pellman 2014; Korzeniewski, et al 2013; Marina and Saavedra 2014; Nigg, et al 2014; Ogden, et al 2012, 2013). Average centrosome number/cell correlates with tumor grade, Ki67 index, and CIN in breast cancer and is highest in the aggressive TNBC subtype (nearly two-thirds of which exhibit >2 centrosomes/cell on average), suggesting that numerical centrosome amplification is associated with aggressive breast cancer features (Denu et al 2016).…”

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

“…Cilia play essential roles in vertebrate development, including establishment of left-right asymmetry, and brain and kidney development [3][4][5]. Disruption of cilia structure or motility is associated with a range of human disorders termed ciliopathies, such as primary ciliary dyskinesias, cystic kidney diseases and situs inversus [6][7][8][9].…”