title: Disruption of spindle pole symmetry by centriole overduplication induces chromosome instability in human malignancies
creator: Cosenza, Marco Raffaele
subject: ddc-500
subject: 500 Natural sciences and mathematics
subject: ddc-570
subject: 570 Life sciences
subject: ddc-610
subject: 610 Medical sciences Medicine
description: Chromosomal instability (CIN) comprises an elevated rate of chromosome missegregation and correlates with the presence of extra centrosomes. Bipolar anaphases with clustered supernumerary centrosomes have been identified as a mechanism contributing to CIN via the formation of transient multipolar spindle intermediates, which promote merotelic kinetochore-microtubule attachment errors.   However, the contribution of this model and that of potential additional mechanisms in human malignancies has not been addressed.   Here we show that centriole rosettes, defined as multiple procentrioles engaged to a single parent, generate spindle asymmetry that favors kinetochore-microtubule attachment errors without centrosome clustering and ultimately results in CIN. Furthermore, we demonstrate that centriole rosettes, but not the progeny of clustered mitoses, are a common finding in primary human malignancies.   Centriole rosettes are capable of arranging bipolar mitotic spindles but cause an increased frequency of anaphase lagging chromosomes and chromosome missegregation. The CIN phenotype is aggravated when spindle pole have asymmetric centriole numbers and it is not rescued by enhancement of kinetochore-microtubule attachment correction.   Furthermore, by immunostaining for an array of centrosomal proteins, we find that, in primary human malignancies, centrosome amplification is characterized by supernumerary procentrioles forming rosettes around a single pair of parental centrioles, strongly arguing for a major contribution of this mechanism in the generation of CIN in vivo.   Our results indicate that asymmetric centriole rosettes produce unbalanced microtubule numbers on mitotic half-spindles, thereby skewing the chance of binding microtubules from the more prominent spindle pole, resulting in impaired correction of merotelic kinetochore attachments and subsequent chromosome missegregation. We propose that centriole numbers at spindle poles must be carefully controlled to ensure chromosome segregation fidelity and disruption of this mechanism is an important source of CIN in human cancer.   
date: 2015
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/19144/1/COSENZA%20-%20PhD%20THESIS%202015.pdf
identifier: DOI:10.11588/heidok.00019144
identifier: urn:nbn:de:bsz:16-heidok-191447
identifier:   Cosenza, Marco Raffaele  (2015) Disruption of spindle pole symmetry by centriole overduplication induces chromosome instability in human malignancies.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/19144/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng