Centromeric Non-coding Transcription: Opening the Black Box of Chromosomal Instability?

Abstract

In eukaryotes, mitosis is tightly regulated to avoid the generation of numerical chromosome aberrations, or aneuploidies. The aneuploid phenotype is a consequence of chromosomal instability (CIN), i.e., an enhanced rate of chromosome segregation errors, which is frequently found in cancer cells and is associated with tumor aggressiveness and increased tumor cell survival potential. To avoid the generation of aneuploidies, cells rely on the spindle assembly checkpoint (SAC), a widely conserved mechanism that protects the genome against this type of error. This signaling pathway stops mitotic pro-gression before anaphase until all chromosomes are correctly attached to spindle microtubules. Howev-er, impairment of the SAC cannot account for the establishment of CIN because cells bearing this phe-notype have a functional SAC. Hence, in cells with CIN, anaphase is not triggered until all chromo-somes are correctly attached to spindle microtubules and congressed at the metaphase plate. Thus, an in-teresting question arises: What mechanisms actually mediate CIN in cancer cells? Recent research has shown that some pathways involved in chromosome segregation are closely associated to centromere-encoded non-coding RNA (cencRNA) and that these RNAs are deregulated in abnormal conditions, such as cancer. These mechanisms may provide new explanations for chromosome segregation errors. The present review discusses some of these findings and proposes novel mechanisms for the establish-ment of CIN based on regulation by cencRNA.

Keywords: Centromere; Chomosome segregation; Chromosome instability; Non-coding RNA.

Fig. (1)

Model for the establishment of chromosomal instability through the deregulation of cencRNA and the deregulation of CENP-A deposition: several different factors can affect the regulation of cencRNAs, including errors in histone marks that control their expression or stress conditions (such as heat shock). The deregulation of such RNAs causes a defective CENP-A replenishment at the end of mitosis/early G1 as a consequence of inadequate CENP-A chaperone recruitment. Because the same amount of CENP-A is replenished in every cell cycle, it is arguable that a single cencRNA deregulation event may promote the perpetuation of an aberrant CENP-A array and consequently, induce chromosomal instability. However, this hypothesis has not been tested to date.

Fig. (2)

Model for the establishment of chromosomal instability through the deregulation of Aurora B activity and cytokinesis failure: both the localization and the kinase activity of Aurora B are promoted by its interaction with cencRNAs. Among other targets, Aurora B phosphorylates CENP-A on its serine 7 residue, and this phosphorylation is necessary for an as-yet unexplained function of CENP-A in cytokinesis. The pharmacological inhibition of Aurora B activity prevents such CENP-A phosphorylation, thereby promoting cytokinesis failure. This defect leads to polyploidy, which in turn promotes the development of multipolar spindles and/or merotelic kinetochore attachments and thus, chromosome mis-segregation. It would be interesting to test whether Aurora B inhibition through depletion of cencRNA has the same effect as its pharmacological inhibition.