Abstract
Nucleoli form around actively transcribed ribosomal RNA (rRNA) genes (rDNA), and the morphology and location of nucleolus-associated genomic domains (NADs) are linked to the RNA Polymerase I (Pol I) transcription status. The number of rDNA repeats (and the proportion of actively transcribed rRNA genes) is variable between cell types, individuals and disease state. Substantial changes in nucleolar morphology and size accompanied by concomitant changes in the Pol I transcription rate have long been documented during normal cell cycle progression, development and malignant transformation. This demonstrates how dynamic the nucleolar structure can be. Here, we will discuss how the structure of the rDNA loci, the nucleolus and the rate of Pol I transcription are important for dynamic regulation of global gene expression and genome stability, e.g., through the modulation of long-range genomic interactions with the suppressive NAD environment. These observations support an emerging paradigm whereby the rDNA repeats and the nucleolus play a key regulatory role in cellular homeostasis during normal development as well as disease, independent of their role in determining ribosome capacity and cellular growth rates.
Highlights
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Nucleoli form around ribosomal RNA genes and dictate the nucleolar morphology and the positioning of nucleolar-associated chromatin domains (NADs) within the nucleus. rRNA genes were first visualized in yeast in the late 1960s by Miller and Beatty using Miller spreads, which provided structural details of actively transcribed rRNA genes, showing a single rDNA repeat transcribed by a multitude of RNA Polymerase I (Pol I) complexes, which they described as the Christmas tree structure [1]
The transcribed 47S precursor rRNA is rapidly processed into the mature 28S, 5.8S and 18S rRNA, which assemble together with the 5S rRNA synthesized by RNA Polymerase III and approximately which assemble together with the 5S rRNA synthesized by RNA Polymerase III and approximately 79 ribosomal proteins translated from mRNAs transcribed by RNA Polymerase II (Pol II) into the 40S and 60S ribosomal subunits
Summary
Genetic information is encoded in a linear DNA sequence, the transcription of particular genes (or gene clusters) depends on the surrounding chromatin structure and higher-order chromosomal interactions. RRNA genes were first visualized in yeast in the late 1960s by Miller and Beatty using Miller spreads, which provided structural details of actively transcribed rRNA genes, showing a single rDNA repeat transcribed by a multitude of RNA Polymerase I (Pol I) complexes, which they described as the Christmas tree structure [1]. Analysis of over 700 tumours and corresponding normal tissues revealed a coupling of 5S rDNA array expansion with a loss of 45S repeats, which was most prevalent in TP53 mutant cancers These variations were considered within the limits of natural variability and did not mediate an overall decrease in rDNA transcriptional output per cell. Genome-wide sequencing analysis [13,14] and genetic studies [31] suggest that the once considered conserved rDNA arrays are one of the most variable regions of the genome
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