Kinetochore Malfunction in Human Pathologies

Abstract

The cell cycle culminates in mitosis with the purpose of dividing the cell's DNA content equally over two daughter cells. Error-free segregation relies on correct connections between chromosomes and spindle microtubules. Kinetochores are complex multi-protein assemblies that mediate these connections and are the platforms for attachment-error-correction and spindle assembly checkpoint signaling. Proper kinetochore function is therefore key in preventing aneuploidization. Mutations in genes encoding kinetochore proteins are associated with several severe developmental disorders associated with microcephaly, and kinetochore defects contribute to chromosomal instability in certain cancers. This chapter gives an overview of the processes necessary for faithful chromosome segregation and how kinetochore malfunction causes various human pathologies.

Spindle checkpoint silencing at kinetochores with submaximal microtubule occupancy

“…Errors in chromosome segregation cause aneuploid karyotypes, which are devastating to embryonic development and are strongly associated with cancer (de Wolf and Kops, 2017;Duijf et al, 2013;Hanahan and Weinberg, 2011;Ricke and van Deursen, 2013). To ensure proper chromosome segregation, the spindle assembly checkpoint (SAC) prevents anaphase initiation until all chromosomes are stably attached to spindle microtubules.…”

Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

“…It is interesting to note that many SAC components that are activated by incomplete attachment of microtubules to kinetochores, and kinetochore factors (BUB1, CENPL, CEP152, NUF2, SPC24, SPC25, NEK2, INCENP, SGO1L, MLF1IP, CASC5, NDC80, and ASPM), are all highly overexpressed in MDR canines ( Supplemental Tables S2 and S3). Elevated expression of SAC and kinetochore components (NCAPG, NCAPG, SKA3, AURKB, NEK2) is associated with cancer [50][51][52][53][54][55], and is consistent with APC impairment.…”

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

“…A growing number of kinetochore factors have been recently associated with cases of microcephaly, so that they can be considered newly rising players in developmental disorders [4,5,51,53,76,77]. Prior to examining the role of each of these factors, we will first briefly review kinetochore functions.…”

“…Their functions have been discussed in depth in several excellent reviews, to which we address the reader for more information [79,83,85,92]. Beyond the well-established role of defective kinetochore functions in generating chromosome instability in cancer, recent studies have revealed mutations in kinetochore-associated genes in several microcephaly syndromes (reviewed in [77]). This has opened a new avenue of experimental work to understand the relationships between defective chromosome segregation and reduced brain growth that we intend to address.…”