The ‘kinetochore maintenance loop’—The mark of regulation?

Abstract

Kinetochores can form and be maintained on DNA sequences that are normally non-centromeric. The existence of these so-called neo-centromeres has posed the problem as to the nature of the epigenetic mechanisms that maintain the centromere. Here we highlight results that indicate that the amount of CENP-A at human centromeres is tightly regulated. It is also known that kinetochore assembly requires sister chromatid cohesion at mitosis. We therefore suggest that separation or stretching between the sister chromatids at metaphase reciprocally determines the amount of centromere assembly in the subsequent interphase. This reciprocal relationship forms the basis of a negative feedback loop that could precisely control the amount of CENP-A and faithfully maintain the presence of a kinetochore over many cell divisions. We describe how the feedback loop would work, propose how it could be tested experimentally and suggest possible components of its mechanism.

Cdk Activity Couples Epigenetic Centromere Inheritance to Cell Cycle Progression

“…We further demonstrate that the only aspect of mitotic passage that is essential for subsequent CENP-A assembly is the resulting loss of mitotic Cdk activity. This does not exclude the possibility that other aspects of mitosis fine-tune CENP-A homeostasis as previously suggested (Brown and Xu, 2009). Because APC/C-mediated destruction of proteins, other than the Cdk1 activator cyclin B, is not required for CENP-A assembly we argue that the trigger initiating assembly likely depends directly on a phosphoswitch mediated by overlapping Cdk1 and Cdk2 kinase activity.…”

A comprehensive molecular cytogenetic analysis of chromosome rearrangements in gibbons

“…Indeed, the uncertainty in drawing a reliable phylogenetic tree of gibbons either with cytogenetic or molecular data is most likely due to the lineage sorting, a phenomena that has apparently occurred at both levels during the rapid evolutionary radiation of gibbons There is no doubt that the small ape lineage has experienced an incredible burst of chromosomal rearrangements. A host of evolutionary processes and mechanisms may have operated to fix these changes including meiotic drive, recombination reduction, molecular divergence in rearranged chromosomes methylation and epigenetic architecture, as well as the demographic parameter Brown and Xu 2009;Carbone et al 2009b;Israfil et al 2011). A comprehensive picture of small ape evolution should also probably include consideration of demographic dynamics and the structure of reproductive units.…”

Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis

“…Centromeric CENP-A levels could also be normalized during S phase passage, in which the mix of parental and G1-loaded pools of CENP-A would be coordinately and preferentially segregated to the granddaughter centromere which inherited a decreased number of CENP-A molecules from the previous generation. An elegant model has been proposed linking the amount of CENP-A assembly in G1 phase directly to the strength of the centromere in mitosis (Brown and Xu, 2009). In this model, weaker centromeres would bind a smaller number of microtubules that would in turn generate a signal driving the assembly of a compensatory number of CENP-A molecules in the subsequent G1 phase ( Figure 1C).…”