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Molecular mechanisms underlying nucleotide repeat expansion disorders

An Author Correction to this article was published on 06 July 2021

This article has been updated

Abstract

The human genome contains over one million short tandem repeats. Expansion of a subset of these repeat tracts underlies over fifty human disorders, including common genetic causes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72), polyglutamine-associated ataxias and Huntington disease, myotonic dystrophy, and intellectual disability disorders such as Fragile X syndrome. In this Review, we discuss the four major mechanisms by which expansion of short tandem repeats causes disease: loss of function through transcription repression, RNA-mediated gain of function through gelation and sequestration of RNA-binding proteins, gain of function of canonically translated repeat-harbouring proteins, and repeat-associated non-AUG translation of toxic repeat peptides. Somatic repeat instability amplifies these mechanisms and influences both disease age of onset and tissue specificity of pathogenic features. We focus on the crosstalk between these disease mechanisms, and argue that they often synergize to drive pathogenesis. We also discuss the emerging native functions of repeat elements and how their dynamics might contribute to disease at a larger scale than currently appreciated. Lastly, we propose that lynchpins tying these disease mechanisms and native functions together offer promising therapeutic targets with potential shared applications across this class of human disorders.

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Fig. 1: Molecular mechanisms of nucleotide repeat expansion pathogenesis.
Fig. 2: Repeat-induced transcriptional gene silencing, R-loops and somatic instability.
Fig. 3: Mechanisms of RNA toxicity in repeat expansion diseases.
Fig. 4: Mechanisms of repeat-associated non-AUG translation.
Fig. 5: Synergy across pathogenic mechanisms of repeat expansion diseases.
Fig. 6: Roles of repeats in human disease and neuronal function.

Change history

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Acknowledgements

This work was supported by US National Institutes of Health grants NS099280, NS086810 and P50HD104463 and VA grant BLRD BX004842 to P.K.T., and US National Institutes of Health grants AG058636, R01NS112291 and R01NS114253 to E.T.W. I.M. was supported by the Alzheimer’s Association Research Fellowship (AARF-20-684648). C.P.K. is supported by the US National Science Foundation Graduate Research Fellowship Program.

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The authors contributed equally to all aspects of the article.

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Correspondence to Eric T. Wang or Peter K. Todd.

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P.K.T. holds a shared patent with Ionis Pharmaceuticals on ASO technologies for use against RAN translation. He also serves as a paid consultant for Denali Therapeutics, holds stock options in this company and has received licensing fees for use of experimental tools developed by his research group. The other authors declare no competing interests.

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Nature Reviews Molecular Cell Biology thanks Clotilde Lagier-Tourenne and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Non-canonical translation

Translation initiation that does not require one or more canonical RNA features, such as a 5′ cap or an AUG start codon.

Somatic instability

DNA repair-mediated differences in the number of short tandem repeats between cells of an individual which develop over their lifetime.

Ribonucleoprotein

(RNP). A transient or stable complex formed by multivalent interaction of proteins and RNAs.

Repeat-associated non-AUG (RAN) translation

A form of non-canonical translation initiated at an expanded-repeat RNA in the absence of an AUG start codon.

Transcriptional gene silencing

The process of inhibiting RNA polymerase-mediated RNA synthesis, which results in abolition of or partial decrease in RNA production.

R-loop

A three-stranded RNA–DNA hybrid structure containing two strands of DNA and one strand of RNA, the latter of which forms Watson–Crick base pairs with the complementary DNA strand.

Rare fragile site

Refers to rare heritable expanded repeat loci that tend to break when cells are exposed to replication stress, such as growth in a folate-free medium.

DNA mismatch repair

(MMR). Repair pathway of erroneous insertions, deletions and base misincorporations during DNA replication and transcription. MMR has a role in resolving R-loops and repairing DNA damage caused by oxidative stress.

RNA foci

RNA clusters formed by accumulation of expanded-repeat RNAs or ribonucleoprotein complexes, primarily in the nucleus and sometimes in the cytoplasm.

Secondary structures

The patterns of intramolecular base pairing of nucleotides within an RNA molecule.

G-quadruplexes

Stable nucleic acid secondary structures formed by the stacking of several planar guanine quadruplets.

A-form double helix

A right-handed, compact helical structure formed by RNA–DNA and RNA–RNA duplexes.

Phase separation

The thermodynamic process by which a homogeneous mixture of components separates spontaneously into different coexisting phases. In aqueous solutions of biomolecules, phase separation is often driven by intrinsically disordered proteins and/or multivalent interactions between proteins and RNAs.

Phase diagram

A graphical depiction of the phases accessible to a system as a function of multiple thermodynamic properties.

Near-cognate start codons

Also known as near-AUG codons, these codons differ from the canonical AUG start codon by a single base, for example, a CUG codon.

Upstream open reading frames

(uORFs). Small open reading frames in the 5′ untranslated region of an mRNA capable of undergoing translation.

Internal ribosomal entry site

(IRES). A structured RNA element that allows non-canonical translation initiation from within the mRNA without requiring a 5′ cap.

Stress granules

Membraneless ribonucleoprotein compartments that appear in the cytosol in response to various cellular stresses.

Frameshifting

Shifts or slips of translating ribosomes along the mRNA which change the open reading frame and the sequence of the translated protein.

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Malik, I., Kelley, C.P., Wang, E.T. et al. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00382-6

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