Stress-induced acidification may contribute to formation of unusual structures in C9orf72-repeats

Zamiri, Bita; Mirceta, Mila; Abu-Ghazalah, Rashid M.; Wold, Marc S.; Pearson, Christopher E.; Macgregor, Robert B.

doi:10.1016/j.bbagen.2018.03.001

Cited by 8 publications

(7 citation statements)

References 74 publications

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“…Based on described structural differences we can expect that AQU and NAN could bind and recruit different proteins. It was shown, for example, that replication protein A, a ssDNA binding protein known to unfold G-quadruplexes ( 62 ), binds to d(G 4 C 2 ) 8 in vitro with significantly higher affinity at pH 5.0 compared to 7.8, suggesting it recognizes a structure which is preferred at acidic conditions ( 63 ). A cell could respond to acidification by using different molecular pathways triggered by binding to AQU compared to NAN.…”

Section: Discussionmentioning

confidence: 99%

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

Brčić

Plavec

2018

Nucleic Acids Research

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Most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a largely increased number of d(G4C2)n•(G2C4)n repeats located in the non-coding region of C9orf72 gene. Non-canonical structures, including G-quadruplexes, formed within expanded repeats have been proposed to drive repeat expansion and pathogenesis of ALS and FTD. Oligonucleotide d[(G4C2)3G4], which represents the shortest oligonucleotide model of d(G4C2) repeats with the ability to form a unimolecular G-quadruplex, forms two major G-quadruplex structures in addition to several minor species which coexist in solution with K+ ions. Herein, we used solution-state NMR to determine the high-resolution structure of one of the major G-quadruplex species adopted by d[(G4C2)3G4]. Structural characterization of the G-quadruplex named AQU was facilitated by a single substitution of dG with 8Br-dG at position 21 and revealed an antiparallel fold composed of four G-quartets and three lateral C–C loops. The G-quadruplex exhibits high thermal stability and is favored kinetically and under slightly acidic conditions. An unusual structural element distinct from a C-quartet is observed in the structure. Two C•C base pairs are stacked on the nearby G-quartet and are involved in a dynamic equilibrium between symmetric N3-amino and carbonyl-amino geometries and protonated C+•C state.

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Section: Discussionmentioning

confidence: 99%

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

Brčić

Plavec

2018

Nucleic Acids Research

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“…In vitro , GGGGCC repeat RNA forms secondary structures, including hairpins45,66 and highly stable G-quadruplexes45,66,161–163. Other secondary structures, including DNA–RNA heteroduplexes, RNA duplexes and i-motifs164–167, might arise from the sense and antisense repeat RNA and DNA sequences. In vivo , such secondary structures are likely to mediate the sequestration — and, as a consequence, depletion — of RNA-binding proteins (RBPs)66,161 (Box 2), thus providing a clear potential route to RNA toxicity (reviewed extensively elsewhere164,168).…”

Section: Pathogenesis Of C9ftd/alsmentioning

confidence: 99%

C9orf72-mediated ALS and FTD: multiple pathways to disease

Balendra¹,

2018

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The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.

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“…It is known that the antisense sequence of the repeat (CCCCGG) n is transcribed and forms antisense foci but these antisense RNA repeats cannot form G-quadruplexes and their structural conformation has not yet been formally resolved [ 50 ]. While the C-rich antisense DNA strand of the repeat has been shown to form an i-motif structure, RNA is thought less likely to form such structures under physiological conditions [ [63] , [64] , [65] ].…”

Section: Rna Toxicitymentioning

confidence: 99%

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

Douglas

2018

Non-coding RNA Research

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A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72-related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats. Formation of RNA/DNA hybrid R-loops may also play a key role in the pathogenesis of this condition and this mechanism could provide a link between the repeat expansion, DNA damage, repeat instability and deficiency of RNA binding proteins. Non-coding C9orf72 antisense transcripts could also act to epigenetically regulate gene expression at the locus. The potential effects of such non-coding RNAs should be considered in the design of antisense oligonucleotide therapeutics for C9orf72-related ALS/FTD. Furthermore, the mechanisms of RNA dysregulation exemplified by C9orf72-related disease may help illustrate more broadly how a “perfect storm” of dysfunction occurs in ALS/FTD and how targeting these factors could lead to corrective or preventative therapies.

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Stress-induced acidification may contribute to formation of unusual structures in C9orf72-repeats

Cited by 8 publications

References 74 publications

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

NMR structure of a G-quadruplex formed by four d(G4C2) repeats: insights into structural polymorphism

C9orf72-mediated ALS and FTD: multiple pathways to disease

Non-coding RNA in C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia: A perfect storm of dysfunction

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