The Role of Human Centromeric RNA in Chromosome Stability

Abstract

Chromosome instability is a hallmark of cancer and is caused by inaccurate segregation of chromosomes. One cellular structure used to avoid this fate is the kinetochore, which binds to the centromere on the chromosome. Human centromeres are poorly understood, since sequencing and analyzing repeated alpha-satellite DNA regions, which can span a few megabases at the centromere, are particularly difficult. However, recent analyses revealed that these regions are actively transcribed and that transcription levels are tightly regulated, unveiling a possible role of RNA at the centromere. In this short review, we focus on the recent discovery of the function of human centromeric RNA in the regulation and structure of the centromere, and discuss the consequences of dysregulation of centromeric RNA in cancer.

Keywords: cancer; cenRNA; centromere; chromosome instability; kinetochore; lncRNA.

FIGURE 1

Schematic representation of the constitutive role of cenRNA in the structure of the centromere in humans. Left, the product of transcription of alpha-satellite DNA by the RNA polymerase II recruits CENP-A. Middle, after the constitution of the CENP-A nucleosome, cenRNA recruits CENP-C. Right, during mitosis, cenRNA may still be associated with the CCAN, and recruit the CPC via interaction with Aurora B to build the whole kinetochore.

FIGURE 2

cGas-STING activation pathway. In green is the normal pathway, where cytosolic DNA created by the misregulation of cenRNA is detected by cGAS, which will cause the activation of STING (Corrales et al., 2015; Jiang et al., 2020). This is detrimental for cancer cells that will inactive STING using different strategies, in red (Saitoh et al., 2009; Xiong et al., 2018). One possible rescue is to inject synthetic CDN to force the activation of STING, shown in blue (Corrales et al., 2015).