Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 30 (14), 1598-610

Nucleolar Organizer Regions: Genomic 'Dark Matter' Requiring Illumination

Affiliations
Review

Nucleolar Organizer Regions: Genomic 'Dark Matter' Requiring Illumination

Brian McStay. Genes Dev.

Abstract

Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans. In higher eukaryotes, NORs are typically located within regions of chromosomes that form perinucleolar heterochromatin during interphase. Typically, the genomic architecture of NORs and the chromosomal regions within which they lie is very poorly described, yet recent evidence points to a role for context in their function. In Arabidopsis, NOR silencing appears to be controlled by sequences outside the rDNA (ribosomal DNA) array. Translocations reveal a role for context in the expression of the NOR on the X chromosome in Drosophila Recent work has begun on characterizing the genomic architecture of human NORs. A role for distal sequences located in perinucleolar heterochromatin has been inferred, as they exhibit a complex transcriptionally active chromatin structure. Links between rDNA genomic stability and aging in Saccharomyces cerevisiae are now well established, and indications are emerging that this is important in aging and replicative senescence in higher eukaryotes. This, combined with the fact that rDNA arrays are recombinational hot spots in cancer cells, has focused attention on DNA damage responses in NORs. The introduction of DNA double-strand breaks into rDNA arrays leads to a dramatic reorganization of nucleolar structure. Damaged rDNA repeats move from the nucleolar interior to form caps at the nucleolar periphery, presumably to facilitate repair, suggesting that the chromosomal context of human NORs contributes to their genomic stability. The inclusion of NORs and their surrounding chromosomal environments in future genome drafts now becomes a priority.

Keywords: human acrocentric chromosomes; nucleolar organizer regions (NORs); nucleolus; ribosomal genes; upstream binding factor (UBF).

Figures

Figure 1.
Figure 1.
The location of NORs and the nucleolar cycle in human cells. (A) Schematic showing a human rDNA array expanded to show the pre-rRNA-coding sequences that are transcribed by RNA Pol I. The positions of mature rRNA-coding sequences, ETSs, and ITSs are indicated. (B) The locations of NORs on the acrocentric chromosome are indicated. The short arms, circled in red, are missing from the current genome draft GRCh38.p7. (C) During cell division, transcription ceases, and nucleoli disappear. NORs can be observed as achromatic gaps on DAPI-stained metaphase chromosomes due to undercondensation of rDNA (red dotted line). Silent NORs (solid red) fail to show this morphology and do not contribute to nucleolar formation. Transcription resumes in anaphase, and nucleoli form around individual active NORs. In most cell types, these then fuse, producing characteristic large nucleoli surrounded by heterochromatin.
Figure 2.
Figure 2.
Chromosomal context determines NOR activity status in A. thaliana. (A) The location of NORs (blue) on the top/north arms of chromosomes 2 and 4 (NOR2 and NOR4, respectively). In strain Col-0, NOR2 containing rDNA variants VAR1 and VAR3 is silent (red lettering). NOR4 containing VAR2 and VAR3 rDNA repeats is active (green lettering). In the strain ColSf-NOR4, NOR4 and adjacent sequences from strain Sf-2 (yellow) were introgressed (engineered) into the Col-0 genetic background. The SF-2 NOR4 (yellow) is comprised solely of VAR1 repeats. VAR1 repeats are active (green lettering) in the ColSf-NOR4 context. (B) A model proposing that a NOR inactivation center immediately proximal to NOR2 is responsible for its silencing (Chandrasekhara et al. 2016).
Figure 3.
Figure 3.
The chromosomal context of human NORs located on acrocentric short arms. (A) Schematic human acrocentric chromosome short arm showing the NOR (rDNA array), expanded below into rDNA repeats, and the PJ (orange) and DJ (green) regions. The DJ region is further expanded to show the location of inverted repeats (light green arrows), DJ promoters and transcripts, Acro138 repeat blocks (red), and CER satellite (blue). (B) Cartoon showing the transition from normal nucleolar organization to segregated nucleolar organization in response to AMD treatment or the introduction of rDNA double-strand breaks (DSBs). rDNA (red) retreats from the nucleolar interior (black) to the nucleolar periphery, forming caps adjacent to DJ sequences (green) that are embedded in PNH (dark blue) (Floutsakou et al. 2013; van Sluis and McStay 2015).
Figure 4.
Figure 4.
Structure of the ribosomal DNA gene cluster in S. cerevisiae. The location of the rDNA cluster on chromosome XII is shown at the top, with the telomere (TEL) and centromere (CEN) indicated. A detailed view of an rDNA repeat unit is shown below. The 35S and 5S rRNA gene-coding regions are indicated, as is the rDNA origin of replication (rARS). The RFB (red box) is bound by Fob1p (pink). The locations of the 35S promoter and the bidirectional noncoding promoter E-pro (blue box), silenced by Sir2p, are indicated.

Similar articles

See all similar articles

Cited by 52 articles

See all "Cited by" articles

Publication types

LinkOut - more resources

Feedback