HMG-boxes, ribosomopathies and neurodegenerative disease

Abstract

The UBTF E210K neuroregression syndrome is a predominantly neurological disorder caused by recurrent de novo dominant variants in Upstream Binding Factor, that is, essential for transcription of the ribosomal RNA genes. This unusual form of ribosomopathy is characterized by a slow decline in cognition, behavior, and sensorimotor functioning during the critical period of development. UBTF (or UBF) is a multi-HMGB-box protein that acts both as an epigenetic factor to establish "open" chromatin on the ribosomal genes and as a basal transcription factor in their RNA Polymerase I transcription. Here we review the possible mechanistic connections between the UBTF variants, ribosomal RNA gene transcription and the neuroregression syndrome, and suggest that DNA topology may play an important role.

Keywords: RNA polymerase I (POLR1); TBP-TAF complex SL1; UBTF-E210K; neuroregression syndrome; ribosome biogenesis; ribosomopathy; upstream binding factor (UBF/UBTF).

FIGURE 1

(A) Organisation of the transcriptionally active ribosomal RNA gene (rDNA) showing the 47S primary transcript, 18S, 5.8S and 28S coding regions, and the 47S promoter (47SPr) flanked upstream by the Enhancer region and its associated Spacer Promoter (SpPr). The nucleosomal Inter-Genic Spacer (IGS) is also shown flanking the UBTF-bound nucleosome-free region (NFR). (B) A schematic representation of the RNA polymerase I (RPI) preinitiation complex and the 47S promoter Upstream and Core regions.

FIGURE 2

UCSC Genome Browser display of the Human UBTF locus on chr17 (http://genome.ucsc.edu), showing the consensus coding sequence (CCDS) annotations in green above the ClinVar variants (Landrum et al., 2018). Gains are noted in blue and losses in red. ClinVar single nucleotide variants (SNVs) classified (ClinVar interp) as P (Pathogenic), LP (Likely Pathogenic), VUS (Variant of Unknown Significant), LB (Likely Benign), B (Benign), and Other.

FIGURE 3

Structural models of the UBTF-DNA nucleoprotein complex. (A) The structural domains of UBTF1 and 2 variants. (B) The Enhancesome structure deduced from ESI studies on UBTF trunaction variants and indicating the bending of DNA, shown in red. (C) The AlphaFold predicted structure of HMGB-box 2.1. The central spliced subdomain is indicated in yellow, the hydrophobic core is ringed and the structure predication for the spliced box 2.2 is shown in green.

FIGURE 4

An induced-fit model for RPI PIC formation. Initial interaction of UBTF with the Promoter DNA would transiently induce its bending and provide a topology that improves SL1-DNA interactions, leading to the formation of a stable tripartite SL1-DNA-UBTF PIC structure and subsequent RPI recruitment. In the first three diagrams only the HMGB-boxes 1 to 3 of UBTF required for the Enhancesome fold are shown (blue), while in the last diagram boxes 4 to 6 are indicated along with potential contacts between the C-terminal UBTF acidic tail and RPI (light grey).

FIGURE 5

The potential effects of the E210K and Q203R UBTF variants on HMGB-box 2 structure. (A) Predicated structures of the variant boxes showing the mutated sidechain (space-filling spheres) and hydrophobic core (ringed). The upper panels show the wild-type box 2 structure predictions and the lower panels the predictions for the variants. In each case the side chains of the affected residues are modelled as space-filling. The two variant structures are shown rotated ∼180 deg. relative to each other to better reveal position of the variant side chains. (B) Comparative primary structure alignment of HMGB-box 1 and 2 indicating residues implicated in the respective hydrophobic cores (red) and mutated residues (yellow). Basic residues probably involved in contacting the DNA are also indicated (blue) and their sidechains shown in A.