Molecular Dynamics Studies of Trinucleotide Repeat DNA Involved in Neurodegenerative Disorders

Jithesh, Puthen V.; Singh, Prachi; Joshi, Rajendra

doi:10.1080/07391102.2001.10506756

Cited by 8 publications

(2 citation statements)

References 67 publications

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“…The dodecamer repeat forms more secondary structures than any of the disease associated triplet repeats, including hairpins stabilized primarily by G W G base pairs, G-tetraplexes and i-tetraplexes, and both Y W R W Y and R W R W Y triplexes (Jithesh et al, 2001;Pataskar et al, 2001aPataskar et al, 2001bSaha and Usdin, 2001). Both intrastrand tetraplexes, which can be thought of as folded hairpins or hairpin dimers, and G-tetraplexes have extraordinary stability relative to hairpins.…”

Section: The Dodecamer Repeat Expansion Is In the Cstb Promotermentioning

confidence: 99%

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

Lalioti

Antonarakis

Scott

2003

Cytogenet Genome Res

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Progressive myoclonus epilepsy 1 (EPM1) or Unverricht-Lundborg disease is a human autosomal recessive neurodegenerative disorder caused by mutations in cystatin B (CSTB). The CSTB gene maps to human chromosome 21 and encodes an inhibitor of lysosomal cysteine proteases. Five point mutations have been found, two of which are seen in numerous unrelated patients. However, the main CSTB mutation in EPM1, even among patients of different ethnic origins, is an expansion of a dodecamer repeat (CCCCGCCCCGCG) in the 5′ flanking area of CSTB. Most normal alleles contain either two or three repeats, while rarer normal alleles that are highly unstable contain between 12 and 17 repeats. Mutant expanded alleles have been reported to contain between 30 and 80 copies and are also highly unstable, particularly via parental transmission. There is no apparent correlation between mutant repeat length and disease phenotype. While the repeat expansion is outside the CSTB transcriptional unit, it results in a marked decrease in CSTB expression, at least in certain cell types in vitro. Cstb homozygous knockout mice show some parallels to the phenotype of human EPM1 including myoclonic seizures, development of ataxia and neuropathological changes associated with cell loss via apoptosis. Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.

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Section: The Dodecamer Repeat Expansion Is In the Cstb Promotermentioning

confidence: 99%

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

Lalioti

Antonarakis

Scott

2003

Cytogenet Genome Res

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“…The dodecamer repeat expansion forms more secondary structures than any of the other triplet repeat expansions, including hairpins, tetraplexes and I-motifs (Jithesh et al 2001;Pataskar et al 2001a,b;Saha and Usdin 2001). Tetraplexes, which seem to be the predominant structures of the EPM1 repeat, are stable at physiological temperatures, pH, and ionic strength (Saha and Usdin 2001).…”

Section: Instability Of the Dodecamer Repeatmentioning

confidence: 99%

Dodecamer Repeat Expansion in Progressive Myoclonus Epilepsy 1

Lalioti

Antonarakis

Scott

Nucleic Acids and Molecular Biology

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Multiscale modeling of nucleic acids: Insights into DNA flexibility

Bomble

Case

2008

Biopolymers

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The elastic rod theory is used together with all-atom normal mode analysis in implicit solvent to characterize the mechanical flexibility of duplex DNA. The bending, twisting, stretching rigidities extracted from all-atom simulations (on linear duplexes from 60 to 150 base pairs in length and from 94 base-pair minicircles) are in reasonable agreement with experimental results. We focus on salt concentration and sequence effects on the overall flexibility. Bending persistence lengths are about 20% higher than most experimental estimates, but the transition from low-salt to high-salt behavior is reproduced well, as is the dependence of the stretching modulus on salt (which is opposite to that of bending). CTG and CGG trinucleotide repeats, responsible for several degenerative disorders, are found to be more flexible than random DNA, in agreement with several recent studies, whereas poly (dA).poly(dT) is the stiffest sequence we have encountered. The results suggest that current all-atom potentials, which were parameterized on small molecules and short oligonucleotides, also provide a useful description of duplex DNA at much longer length scales.

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Molecular Dynamics Studies of Trinucleotide Repeat DNA Involved in Neurodegenerative Disorders

Cited by 8 publications

References 67 publications

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion

Dodecamer Repeat Expansion in Progressive Myoclonus Epilepsy 1

Multiscale modeling of nucleic acids: Insights into DNA flexibility

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