Frontiers in Molecular Biosciences: The Role of Human Centromeric RNA in Chromosome StabilityThe Role of Human Centromeric RNA in Chromosome Stability (Kitagawa Lab)
Accurate chromosome segregation is fundamental for cell division. Errors in this process can lead to chromosome instability, leading to aneuploidy, which is correlated with cancer (Zhu et al., 2011; Santaguida and Amon, 2015). The centromere is a component of each chromosome used for accurate chromosome segregation. The kinetochore, the structure responsible for binding the chromosome to spindle microtubules and for chromosome movement during cell division, is assembled on the centromere (Van Hooser et al., 2001). The identity and inheritance of the centromere are thought to be determined epigenetically by the deposition of the species-specific histone 3 variant CENH3 (CENP-A in mammals, CID in D. melanogaster, and Cse4 in S. cerevisiae) nucleosomes interspersed with classical Histone 3 nucleosomes (Blower et al., 2002; Fukagawa and Earnshaw, 2014; Niikura et al., 2016). The centromere of the budding yeast S. cerevisiae consists of a 100 nucleotides DNA sequence motif and is referred to as a point centromere (Pluta et al., 1995). In all other eukaryotes, centromeres are composed of repetitive DNA sequences on several hundred kilobases, referred to as regional centromeres (Pluta et al., 1995). Furthermore, the DNA composition of each centromere presents a high variation between each chromosome (Eichler, 1999; Melters et al., 2013). The “centromere paradox” refers to how highly diverse centromere sequences are, even in closely related eukaryotes (Eichler, 1999). Human centromeres are composed of α-satellite repeated tandemly to form a block of satellites, called higher-order repeat (HOR) that are composed of a set number of monomers that vary from 2 to 34 (Willard, 1985; Willard et al., 1986; Alexandrov et al., 1993; McNulty et al., 2017). Despite the repetitive sequences composing the centromere, this region is transcriptionally active, with the transcription of genes in rice (Nagaki et al., 2004; Mizuno et al., 2011). For other organisms, centromeric DNA encodes for siRNA (Grishok et al., 2000; Volpe et al., 2002; Zilberman et al., 2003; Fukagawa et al., 2004; Pal-Bhadra et al., 2004) and long non-coding RNA called cenRNA (Wong et al., 2007; Carone et al., 2009).
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