Influence of Sequence Context and Length on the Structure and Stability of Triplet Repeat DNA Oligomers

Paiva, Anthony M.; Sheardy, Richard D.

doi:10.1021/bi0494368

Cited by 69 publications

(106 citation statements)

References 19 publications

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“…In fact, three alternative spliced forms of the transcribed pre-mRNA of HSD3B2 are known to exist (http://www.ebi.ac.uk/asd/), with intron 3 excluded from the two shorter transcribed mRNAs that also contain different coding sequences that might alter HSD3B2 activity and therefore may degrade DHT at varying rates. In terms of which alleles are more likely to form hairpins, previous studies have shown that longer allele length is associated with hairpin structures that are more stable, but this stability is achieved at a certain maximum length such that alleles longer than this threshold offer no further increased stability for the hairpin structure [35,36]. This would support the conservative decision we made to divide the HSD3B2 length polymorphism into "long" and "short" categories.…”

Section: Discussionsupporting

confidence: 55%

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

et al. 2007

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BACKGROUND-Dihydrotestosterone (DHT) is believed to play an important role in prostate carcinogenesis. Five alpha reductase type II (SRD5A2) and 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2) are responsible for the biosynthesis and degradation of DHT in the prostate. Two polymorphisms, a valine (V) for leucine (L) substitution at the 89 codon of the SRD5A2 gene and a (TG)n,(TA)n,(CA)n repeat polymorphism within the third intron of the HSD3B2 gene were evaluated with regard to prostate cancer risk.

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Section: Discussionsupporting

confidence: 55%

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

et al. 2007

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“…First, biophysical (14,17,[22][23][24] and structural (17, 23, 24 -26) analyses have demonstrated that singlestranded 5Ј-CTG forms more stable hairpin structures than single-stranded 5Ј-CAG due to the presence of wobble pairing. Thus, the differential stability of 5Ј-CTG hairpins and…”

Section: Expansion Of Simple Trinucleotide Repeats (Tnrs)mentioning

confidence: 99%

“…First, biophysical (14,17,(22)(23)(24) and structural (17, 23, 24 -26) analyses have demonstrated that singlestranded 5Ј-CTG forms more stable hairpin structures than single-stranded 5Ј-CAG due to the presence of wobble pairing. Thus, the differential stability of 5Ј-CTG hairpins and their lifetimes may allow more frequent 5Ј-CTG loop entrapment and slippage during replication on the lagging strand template (23)(24)(25)(26)(27).…”

mentioning

confidence: 99%

Single-stranded DNA-binding Protein in Vitro Eliminates the Orientation-dependent Impediment to Polymerase Passage on CAG/CTG Repeats

Delagoutte

Goellner

Guo

et al. 2008

Journal of Biological Chemistry

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Small insertions and deletions of trinucleotide repeats (TNRs) can occur by polymerase slippage and hairpin formation on either template or newly synthesized strands during replication. Although not predicted by a slippage model, deletions occur preferentially when 5-CTG is in the lagging strand template and are highly favored over insertion events in rapidly replicating cells. The mechanism for the deletion bias and the orientation dependence of TNR instability is poorly understood. We report here that there is an orientation-dependent impediment to polymerase progression on 5-CAG and 5-CTG repeats that can be relieved by the binding of single-stranded DNAbinding protein. The block depends on the primary sequence of the TNR but does not correlate with the thermodynamic stability of hairpins. The orientation-dependent block of polymerase passage is the strongest when 5-CAG is the template. We propose a "template-push" model in which the slow speed of DNA polymerase across the 5-CAG leading strand template creates a threat to helicase-polymerase coupling. To prevent uncoupling, the TNR template is pushed out and by-passed. Hairpins do not cause the block, but appear to occur as a consequence of polymerase pass-over. Expansion of simple trinucleotide repeats (TNRs)4 is the underlying genetic defect of a number of human neurodegenerative diseases. TNR-associated pathophysiology in human diseases strictly depends on the number of trinucleotide repeats (reviewed in Refs. 1-3). Although expansion can occur in germ cells (4) and in somatic cells with age (5, 6), emerging evidence suggests that rapid cell division in the early embryo can reduce the size of the repeats and modulate disease potential (7). TNR deletion during rapid cell division may serve as a natural defense mechanism for keeping the length of the repeats in check at critical times in development. Reducing the length of the repeat tract in disease genes is being explored as a therapeutic strategy. However, the mechanisms by which deletions rather than expansions are favored during replication remain poorly understood.DNA polymerase and strand slippage has been proposed as the primary mechanism for instability of trinucleotide repeats (1-3). During replication, the TNR units can misalign resulting in an extrahelical DNA loop that increases TNR length if it occurs on the daughter strand and decreases TNR length if it occurs on the template strand (1-3). In both prokaryotic and eukaryotic models, it is well established that TNR instability is sensitive to the length of the repeat (8 -12), to its structure forming potential (13-17), and to its proximity to the origin of replication (18). The factors that regulate the probability and frequency of deletion events, however, remain poorly understood. By a polymerase slippage model, a deletion implies that hairpin formation has occurred on the template strand. Theoretically, for an identical sequence located either on the template or daughter strand, slippage and hairpin formation can occur with equivalent frequen...

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“…Whether we are looking at B -Z junctions [1], DNA hairpins [2,3] or DNA quadruplexes [4], one observation always presents itself-DNA conformation is regulated by sequence and environment. For a DNA oligomer such as (XXXYYY) z , where X is A, C and/or T, Y is G or T and z = 1, 2, 4 or more, the conformation of any secondary structure formed is highly dependent on the identities of X and Y, the number of repeats z and the conditions under which the DNA is prepared (temperature, pH, counterions present and their concentrations, etc.).…”

Section: Introductionmentioning

confidence: 99%

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

Yadav¹,

Sheardy²

2012

JBPC

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The human telomere sequence (TTAGGG) 4 folds into an unusual conformation possessing three G-tetrads linked by TTA loops. The first loop is a propeller loop while the second and third loops are transverse loops. Using Circular Dichroism (CD) spectroscopy, we have investigated the effect of sequence context on the structures and stabilities of intramolecular G-quadruplexes related to the human telomere sequence by considering all permutations of T and A within the loops. The results indicate that changing only one base in any one loop can have a dramatic effect on the conformation of the quadruplex as well as its melting temperature, T m . Thus, each sequence studied has a unique CD spectrum and T m . In general, variants with a modified second loop are the most stable while the wild type sequence is the least stable. The observed difference in CD spectra and melting temperature are discussed in terms of base stacking within the loop and stacking of the loop bases with adjacent G-tetrads.

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Influence of Sequence Context and Length on the Structure and Stability of Triplet Repeat DNA Oligomers

Cited by 69 publications

References 19 publications

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

SRD5A2 and HSD3B2 polymorphisms are associated with prostate cancer risk and aggressiveness

Single-stranded DNA-binding Protein in Vitro Eliminates the Orientation-dependent Impediment to Polymerase Passage on CAG/CTG Repeats

A single base permutation in any loop of a folded intramolecular quadruplex influences its structure and stability

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