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Review
. 2016 Jul;22(7):615-628.
doi: 10.1016/j.molmed.2016.05.005. Epub 2016 Jun 3.

Hypo- and Hyper-Assembly Diseases of RNA-Protein Complexes

Siddharth Shukla  1 , Roy Parker  2
Affiliations
Review

Hypo- and Hyper-Assembly Diseases of RNA-Protein Complexes

Siddharth Shukla et al. Trends Mol Med. 2016 Jul.

Abstract

A key aspect of cellular function is the proper assembly and utilization of ribonucleoproteins (RNPs). Recent studies have shown that hyper- or hypo-assembly of various RNPs can lead to human diseases. Defects in the formation of RNPs lead to 'RNP hypo-assembly diseases', which can be caused by RNA degradation outcompeting RNP assembly. By contrast, excess RNP assembly, either in higher order RNP granules, or due to the expression of repeat-containing RNAs, can lead to 'RNP hyper-assembly diseases'. Here, we discuss the most recent advances in understanding the cause of disease onset, as well as potential therapies from the aspect of modulating RNP assembly in the cell, which presents a novel route to the treatment of these diseases.

Keywords: RNA quality control; RNP assembly; dyskeratosis congenita; spinal muscular atrophy; stress granules; therapy.

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Figures

Figure 1
Figure 1. Mechanism of RNP Hypo-Assembly
RNP hypo-assembly diseases are caused by RNA quality control pathways out-competing defective RNP assembly in the cell. Under normal physiological conditions, cellular RNAs interact with RNA binding proteins to form RNPs. In hypo-assembly diseases, RNP formation is reduced, leading to RNA degradation by competing RNA quality control mechanisms.
Figure 2
Figure 2. Competition Between hTR RNP Assembly and Quality Control
Under normal conditions, hTR is bound by dyskerin and other H/ACA proteins to form the hTR RNP. In DC, unassembled hTR is degraded by EXOSC10 in the nucleus, and by DCP2/XRN1 in the cytoplasm. DCP2 removes the m7Gpp cap structure from the 5’ end of hTR, exposing the monophosphate to allow XRN1-mediated exonucleolytic digestion. Loss of PARN also leads to degradation of hTR by EXOSC10, which is aided by PAPD5-mediated oligoadenylation of hTR 3’ end, where it can destabilize both unbound and assembled hTR molecules.
Figure 3
Figure 3. snRNP Biogenesis Competes with Programmed RNA Quality Control Pathways
Under normal conditions, snRNAs are transcribed and exported to the cytoplasm, where the SMN protein as a part of the SMN complex promotes the binding of Sm complex to the Sm site on snRNAs. Following Sm complex binding, the 5’ cap of snRNAs is modified to m2,2,7Gpp, and snRNPs are re-imported to the nucleus for final maturation. When SMN levels are reduced, snRNAs are degraded in the cytoplasm by DCP2/XRN1 when Sm complex assembly is compromised, as observed in patients suffering from a severe form of SMA.
Figure 4
Figure 4. Formation and Persistence of Stress Granules Potentially Cause RNP Hyper-Assembly Diseases
Disease-causing mutations in RNA binding proteins, such as TDP-43, FUS and hnRNPA1/A2B1, can lead to formation of aberrant RNP granules, which share components of stress granules. Similarly, mutations that lead to increased persistence of stress granules, such as VCP or DNAJB6, can also lead to a variety of human diseases.
Figure 5
Figure 5. Repeat Expansion in mRNAs as a Cause of RNP Hyper-Assembly Diseases
A) CUG repeat expansion in the DMPK mRNA can sequester other RNA-binding proteins like MBNL in RNA foci, and inhibit alternative splicing of pre-mRNAs leading to disease pathology. B) G4C2 repeat expansion in the C9orf72 mRNA could sequester RNA binding proteins in nuclear foci, or can be translated into dipeptide repeats that can also aggregate with other RNA-protein complexes in the cytoplasm. These cytoplasmic aggregates could possibly inhibit nucleo-cytoplasmic transport of cellular components.
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