Keeping ribosomal DNA intact: a repeating challenge

Abstract

More than half of the human genome consists of repetitive sequences, with the ribosomal DNA (rDNA) representing two of the largest repeats. Repetitive rDNA sequences may form a threat to genomic integrity and cellular homeostasis due to the challenging aspects of their transcription, replication, and repair. Predisposition to cancer, premature aging, and neurological impairment in ataxia-telangiectasia and Bloom syndrome, for instance, coincide with increased cellular rDNA repeat instability. However, the mechanisms by which rDNA instability contributes to these hereditary syndromes and tumorigenesis remain unknown. Here, we review how cells govern rDNA stability and how rDNA break repair influences expansion and contraction of repeat length, a process likely associated with human disease. Recent advancements in CRISPR-based genome engineering may help to explain how cells keep their rDNA intact in the near future.

Keywords: Ataxia-Telangiectasia; Bloom Syndrome; CRISPR; DNA repair; DNA repeat integrity; Genomic instability; Repetitive DNA; Ribosomal DNA.

Fig. 1

Graphical illustration of the chromosome locations of the 47S and 5S rDNA repeats. The 47S repeats are distributed over five different chromosomes, whereas the 5S repeats are all located on chromosome 1

Fig. 2

Repair of repeats can result in repeat expansions, contractions, and structural chromosomal aberrations. Configurations between chromosomes with repeats that can cause structural chromosomal rearrangements

Fig. 3

Reversing repeat instability through CRISPR/Cas9. Can a reduction in the number of rDNA repeats in BLM deficient cells by CRISPR/Cas9-induced breaks rescue clinically relevant features including neurodegeneration, cancer, and aging?