The Centrosome Linker and Its Role in Cancer and Genetic Disorders

Mechanisms perturbing both the number and structure of centrosomes are increasingly recognized as the root cause of cancer and many seemingly unrelated human disorders, arguing for a vital role of centrosome integrity in complex physiological processes. The proper spatiotemporal disassembly of the machinery that links duplicated centrosomes together is crucial for both mitotic spindle assembly and symmetric partitioning of duplicated chromosomes in mitosis. Defects in both centrosome separation and cancer-associated genes act synergistically in driving chromosomal instability (CIN), tumor heterogeneity, and cancer evolution. Deciphering the pathogenic mechanisms that allow cancer cells to tolerate centrosome anomalies offers new therapeutic strategies to target cancer types that do not tolerate extreme levels of CIN. Centrosome cohesion, the joining of the two centrosomes of a cell, is increasingly appreciated as a major regulator of cell functions such as Golgi organization and cilia positioning. One major element of centrosome cohesion is the centrosome linker that consists of a growing number of proteins. The timely disassembly of the centrosome linker enables centrosomes to separate and assemble a functional bipolar mitotic spindle that is crucial for maintaining genomic integrity. Exciting new findings link centrosome linker defects to cell transformation and genetic disorders. We review recent data on the molecular mechanisms of the assembly and disassembly of the centrosome linker, and discuss how defects in the proper execution of these processes cause DNA damage and genomic instability leading to disease. Centrosome cohesion, the joining of the two centrosomes of a cell, is increasingly appreciated as a major regulator of cell functions such as Golgi organization and cilia positioning. One major element of centrosome cohesion is the centrosome linker that consists of a growing number of proteins. The timely disassembly of the centrosome linker enables centrosomes to separate and assemble a functional bipolar mitotic spindle that is crucial for maintaining genomic integrity. Exciting new findings link centrosome linker defects to cell transformation and genetic disorders. We review recent data on the molecular mechanisms of the assembly and disassembly of the centrosome linker, and discuss how defects in the proper execution of these processes cause DNA damage and genomic instability leading to disease. the gain or loss of whole chromosomes, resulting in an abnormal number of chromosomes in a cell. However, aneuploidy does not describe whole-genome duplication. a cylindrical structure composed of a radial array of nine triplets of MTs. In humans, the triplets are deployed in a circle with a diameter of ~250 nm and length of ~500 nm. a dynamic and persistent high frequency of chromosome segregation errors that lead to a genomic state in which parts of the chromosomes or even whole chromosomes are duplicated (gain) or deleted (loss). The majority of human solid cancers are characterized by CIN, and this is frequently associated with poor prognosis, metastasis, and therapy resistance. a fibrous cytoskeletal structure that links the base of the cilium to the cell body. In mammals, rootletin, also known as ciliary rootlet coiled-coil protein, is the primary constituent of ciliary rootlets. In interphase cells without cilia, rootletin forms a fibrous link between the centriole pairs to promote centrosome cohesion. a highly complex process by which primary cilia are assembled in G0 phase; this requires the orchestrated production of hundreds of different proteins. a transient and compact MT-based structure formed between separating chromosomes at the end of cytokinesis. The midbody serves as a platform for the assembly of the abscission machinery that controls the final separation of daughter cells. Defects in proteins that regulate the stabilization of the midbody structure have been associated with aneuploidy in cancer. the existence of different subpopulations of cells in a given primary tumor. ITH can be observed at the genetic, proteomic, morphological, and environmental levels. a large protein complex that assembles at the beginning of mitosis over the centromeric region of chromosomes. The centromere is a specialized chromatin structure that contains nucleosomes with the histone 3 variant CENP-A. Kinetochores are required for the interaction of spindle MTs with chromosomes and for proper chromosome segregation. Defects in MT–kinetochore attachments, if not corrected, can lead to chromosome segregation errors. polymers of two proteins named α- and β-tubulins. MTs are highly dynamic structures that are subject to alternating periods of rapid depolymerization and growth, a phenomenon known as dynamic instability. This property of MTs is indispensable for kinetochore capture and chromosome segregation. cells with supernumerary centrosomes form multipolar mitotic spindles that lead to the production of highly aneuploid daughter cells (i.e., multinucleated cells) that are typically inviable. To avoid multipolar divisions, cells cluster their centrosomes into two spindle poles, thereby achieving seemingly normal bipolar division. However, centrosome clustering is prone to chromosome segregation errors, thereby representing a major gateway to tumor development. Compounds that inhibit centrosome clustering are expected to promote the formation of multipolar spindles and cell death. a control mechanism that protects genome integrity in response to delayed mitosis or centrosome loss. accessory proteins such as myosin, kinesin, and dynein that slide along actin filaments (myosin) or MTs (kinesin and dynein), and generate movement and force through the hydrolysis of ATP. the process by which new neurons are formed in the brain. It is crucial during embryo development but also continues in some brain regions after birth and throughout our lifespan. a large protein complex in the nuclear envelope that is responsible for controlled exchange of components between the nucleus and cytoplasm. the abnormal presence of more than two centrosomes and more than four centrioles in a cell. the number of complete sets of chromosomes in a cell. Eukaryotes generally have two sets – pairs of homologous chromosomes – a condition referred to as diploidy. a non-motile solitary extension of the basal body that is found on the surface of nearly every cell in the human body, including sensory cell types. Defects in the structural integrity of this complex extracellular sensor have been associated with numerous pathologies (termed ciliopathies) including cancer. changes in size and composition of the centrosome, without changes in the number of centrioles. this results from a genome-doubling event that generates four complete sets of chromosomes in a single cell. Tetraploidy can be a natural physiological condition but also can be a pathophysiological event in cancer. Tetraploidy is generated by mechanisms such as cell fusion, endoreduplication, mitotic slippage, or cytokinetic failure, the latter two being the main routes in cancer. Tetraploid cells can give to rise to CIN because chromosome mis-segregation events are better tolerated than in diploid cells.