Unpaired Structures in SCA10 (ATTCT)n·(AGAAT)n Repeats

doi:10.1016/S0022-2836(03)00037-8

Journal of Molecular Biology

Volume 326, Issue 4, 28 February 2003, Pages 1095-1111

https://doi.org/10.1016/S0022-2836(03)00037-8 Get rights and content

Abstract

A number of human hereditary diseases have been associated with the instability of DNA repeats in the genome. Recently, spinocerebellar ataxia type 10 has been associated with expansion of the pentanucleotide repeat (ATTCT)_n·(AGAAT)_n from a normal range of ten to 22 to as many as 4500 copies. The structural properties of this repeat cloned in circular plasmids were studied by a variety of methods. Two-dimensional gel electrophoresis and atomic force microscopy detected local DNA unpairing in supercoiled plasmids. Chemical probing analysis indicated that, at moderate superhelical densities, the (ATTCT)_n·(AGAAT)_n repeat forms an unpaired region, which further extends into adjacent A+T-rich flanking sequences at higher superhelical densities. The superhelical energy required to initiate duplex unpairing is essentially length-independent from eight to 46 repeats. In plasmids containing five repeats, minimal unpairing of (ATTCT)₅·(AGAAT)₅ occurred while 2D gel analysis and chemical probing indicate greater unpairing in A+T-rich sequences in other regions of the plasmid. The observed experimental results are consistent with a statistical mechanical, computational analysis of these supercoiled plasmids. For plasmids containing 29 repeats, which is just above the normal human size range, flanked by an A+T-rich sequence, atomic force microscopy detected the formation of a locally condensed structure at high superhelical densities. However, even at high superhelical densities, DNA strands within the presumably compact A+T-rich region were accessible to small chemicals and oligonucleotide hybridization. Thus, DNA strands in this “collapsed structure” remain unpaired and accessible for interaction with other molecules. The unpaired DNA structure functioned as an aberrant replication origin, in that it supported complete plasmid replication in a HeLa cell extract. A model is proposed in which unscheduled or aberrant DNA replication is a critical step in the expansion mutation.

Introduction

Eighteen human genetic diseases have been associated with the expansion of DNA repeats. Diseases associated with non-coding (CGG)_n·(CCG)_n triplet repeats include fragile X syndrome and fragile XE syndrome. Myotonic dystrophy type 1 (DM1), spinocerebellar ataxia (SCA) type 8, and SCA12, involve non-coding (CTG)_n·(CAG)_n repeats. Friedreich's ataxia involves non-coding (GAA)_n·(TTC)_n repeats.1., 2., 3. Huntington's disease; spinocerebellar ataxias 1, 2, 3, 6, 7 and 17;⁴ dentatorubral-pallidoluysian atrophy; and spinobulbar muscular atrophy are associated with expansion of (CAG)_n·(CTG)_n repeats that encode a polyglutamine tract in the affected gene. More recently, spinocerebellar ataxia type 10 (SCA10) and myotonic dystrophy type 2 (DM2) have been associated with the very massive expansion within introns of (ATTCT)_n·(AGAAT)_n and (CCTG)_n·(CAGG)_n repeats, respectively.5., 6. Progressive myoclonus epilepsy is associated with expansion of a G+C-rich dodecamer repeat from two to three copies to more than 70 copies in affected individuals.7., 8., 9.

Spinocerebellar ataxia type 10 has been associated with expansion of the pentanucleotide repeat, (ATTCT)_n·(AGAAT)_n, to as many as 4500 copies.⁵ At present, the molecular mechanisms underlying the propensity of these sequences to expand are not fully understood, but the expansion may be due to errors in DNA replication, perhaps associated with alternative DNA secondary structures, which may present blocks to DNA polymerization.2., 10., 11., 12. All DNA repeats prone to expansions can form alternative DNA structures, which are distinct from the regular B-DNA conformation.¹¹ Single-stranded DNA regions containing (CTG)_n·(CAG)_n and (CGG)_n·(CCG)_n repeats form a significant amount of slipped-strand DNA structure upon re-annealing.¹³ During replication, primer–template misalignment in the repeats may be stabilized by the formation of imperfect (CXG)_n hairpins.11., 14., 15. The G+C-rich sequences, such as GGC, GGA, or GGT may form quadruplex DNA structures,¹⁶ and (GAA)_n·(TTC)_n repeats may form intramolecular triplex structure.17., 18., 19. These alternative DNA secondary structures may trigger a sequence of events leading to expansion.² In particular, they may impede DNA replication16., 20., 21., 22., 23., 24. and/or elicit mismatch25., 26., 27. and nucleotide excision28., 29. repair pathways.

The (ATTCT)_n·(AGAAT)_n repeat is unique among expanding repeat sequences in that it is a pentanucleotide, and it is very A+T-rich. It lacks necessary symmetry elements to form hairpins, intramolecular triplexes, or quadruplexes. Moreover, it does not form slipped-strand DNA because, after strand separation, the double-stranded structure is expected to preferentially nucleate in the flanking sequences with higher G+C contents. The high A+T content is a feature of DNA sequences that form unpaired structures, termed DNA unwinding elements (DUEs) or base unpairing regions (BURs), under superhelical tension.30., 31., 32. DUEs31., 32. are a common feature of bacterial and yeast replication origins³³ and are associated with some human DNA replication origins.³⁴ Using biochemical and biophysical techniques we show that, under physiological conditions, (ATTCT)_n·(AGAAT)_n repeats form unpaired DNA structures in supercoiled DNA. Remarkably, this unpaired DNA structure functions as an aberrant replication origin, supporting complete plasmid replication, in a HeLa cell extract. The implications of aberrant replication origin activity in repeat instability are discussed.

Section snippets

DNA unpairing within (ATTCT)_n·(AGAAT)_n repeats in supercoiled plasmids

Because the SCA10 pentanucleotide repeat (ATTCT)_n·(AGAAT)_n is 80% A+T-rich, this duplex is expected to be thermodynamically less stable than mixed DNA sequence and, therefore, various factors such as torsional stress, temperature, and proteins may promote helix unpairing. DNA unpairing may also be influenced by ionic conditions and the presence of alternative structure-forming sequence elements.30., 35., 36., 37., 38. We compared the structural properties of the (ATTCT)_n·(AGAAT)_n repeats in the

Supercoil dependent DNA unpairing in SCA10 (ATTCT)·(AGAAT) repeats

Several human genetic diseases have been linked to expansions of short nucleotide repeats.1., 3. One possible mechanism of expansion includes slipped misalignment of repeated sequences.11., 48. Contrary to the case of trinucleotide repeat sequences, where the formation of slipped-strand structures was abundant,¹³ we failed to detect an appreciable amount of slipped-strand DNA in (ATTCT)₂₃·(AGAAT)₂₃ repeats upon denaturation and renaturation (data not shown). Using 2D gel electrophoretic

Plasmids

Plasmids pEO5-23 (2890 bp) and pEO5-46 (3005 bp) containing 23 and 46 repeats without flanking human genomic DNA were obtained by first ligating shorter synthetic oligonucleotides to produce 23 and 46 (ATTCT)·(AGAAT) repeats which, after an addition of the terminal EcoRI linkers, were cloned in the EcoRI site of pBR325, as described.²⁹ The repeats were then PCR amplified using a pair of primers containing SmaI and HindIII sites and cloned between the SmaI and HindIII sites of pUC8. Flanking the

Acknowledgements

This work was supported by grants from National Institutes of Health ES05508 (to R.R.S.), NS41547 (to T.A.), GM62235 (to Y.L.L.), HG01973 (to C.J.B.), and GM53819 (to M.L.), and from the National Science Foundation DBI 99-05459 (to C.J.B.).

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Journal of Molecular Biology

Unpaired Structures in SCA10 (ATTCT)n·(AGAAT)n Repeats

Abstract

Introduction

Section snippets

DNA unpairing within (ATTCT)n·(AGAAT)n repeats in supercoiled plasmids

Supercoil dependent DNA unpairing in SCA10 (ATTCT)·(AGAAT) repeats

Plasmids

Acknowledgements

Am. J. Hum. Genet.

J. Mol. Biol.

Am. J. Hum. Genet.

Curr. Opin. Biotechnol.

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

J. Mol. Biol.

FEBS Letters

J. Mol. Biol.

J. Biol. Chem.

J. Mol. Biol.

J. Mol. Biol.

J. Mol. Biol.

Curr. Opin. Struct. Biol.

J. Mol. Biol.

J. Biol. Chem.

Methods

J. Biol. Chem.

Cell

Mutat. Res.

J. Mol. Biol.

Cancer Cell

J. Biol. Chem.

Gene

J. Mol. Biol.

Fourteen and counting: unraveling trinucleotide repeat diseases

Hum. Mol. Genet.

Genetic Instabilities and Hereditary Neurological Diseases

SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein

Hum. Mol. Genet.

Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10

Nature Genet.

Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9

Science

Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy

Nature

Unstable insertion in the 5′ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1

Nature Genet.

Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1

Nature Genet.

Repeat expansion—all in a flap?

Nature Genet.

Slipped strand DNA, dynamic mutations, and human disease

Neurodegenerative diseases. Origins of instability

Nature

Alternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci

Biochemistry

Trinucleotide repeats associated with human disease

Nucl. Acids Res.

NGG-triplet repeats form similar intrastrand structures: implications for the triplet expansion diseases

Nucl. Acids Res.

Intramolecular DNA triplexes in supercoiled plasmids

Proc. Natl Acad. Sci. USA

A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis

Neurology

Unpaired Structures in SCA10 (ATTCT)_n·(AGAAT)_n Repeats

DNA unpairing within (ATTCT)_n·(AGAAT)_n repeats in supercoiled plasmids