Direct evidence for the effect of transcription on local DNA supercoiling in vivo

Rahmouni, A. Rachid; Wells, Robert D.

doi:10.1016/0022-2836(92)90721-u

Cited by 148 publications

(121 citation statements)

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“…Cellular processes such as transcription and replication dramatically alter the local superhelical densities of DNA due to the unwinding of the helices (18,28,29). Also, the extent of instability for a (CTG) n or (CGG) n tract depends on its length and orientation relative to the origin of replication in Escherichia coli (30,31).…”

Section: Discussionmentioning

confidence: 99%

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Gellibolian

Bacolla

Wells

1997

Journal of Biological Chemistry

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The variance of writhe, the contribution of writhe to supercoiling, and the free energies of supercoiling were calculated for (CTG⅐CAG) n and (CGG⅐CCG) n triplet repeat sequences (TRS) by statistical mechanics from the bending and torsional moduli previously determined. Expansions of these sequences are inherited by nonmendelian transmission and are linked with several hereditary neuromuscular diseases. The variance of writhe was greater for the TRS than for random B-DNA. For random B-DNA, (CGG) n , and (CTG) n , the contribution of writhe to supercoiling was 70, 78, and 79%, whereas the free energy of supercoiling at a length of 10 kilobase pairs was 1040⅐RT, 760⅐RT, and 685⅐RT, respectively. These data indicate that the TRS are preferential sites for the partitioning of supercoiling. Calculations of the differences in free energy of supercoiling between the TRS and random B-DNA revealed a local minimum at ϳ520 base pairs. Human medical genetic studies have shown that individuals carrying up to 180 -200 copies of TRS (540 -600 base pairs, premutations) in the fragile X or myotonic dystrophy gene loci are usually asymptomatic, whereas large expansions (>200 repeats, full mutations), which lead to disease, are observed in their offspring. Therefore, the length corresponding to the local minimum in free energy of supercoiling correlates with the genetic breakpoint between premutation and full mutation. We propose that (a) TRS instability is mediated by DNA mispairing caused by the accumulation of supercoiling within the repeats, and (b) the expansions that take place at the premutation to full mutation threshold are associated with increased mispairing caused by the optimal partitioning of writhe within the TRS at this length.Several human loci associated with neurodegenerative disorders have been shown to carry a new form of mutation, i.e. the expansion of a DNA triplet repeat sequence (TRS) 1 with composition (CTG⅐CAG) n , (CGG⅐CCG) n , or (GAA⅐TTC) n , referred to as (CTG) n , (CGG) n , and (GAA) n , respectively (reviewed in Refs. 1-4). These diseases fall into two categories (1).The first, which includes spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease, is characterized by small expansions of a (CTG) n repeat from the ϳ10 -40 in the normal population to ϳ40 -120 units in diseased individuals that encode a polyglutamine tract in the corresponding gene products. This mutation may impart a gain of function to the mature polypeptides that is deleterious to neuronal activity (1-3).The second, which includes the myotonic dystrophy (dystrophia myotonica (DM)) and the fragile X and E (FRAXA and FRAXE) genes, is characterized by much larger expansions of either a (CTG) n or (CGG) n repeat, respectively, in the untranslated region of the genes. The mechanisms by which these expansions lead to disease are not fully understood (5, 6). The number of repeats is polymorphic in the normal population and ranges from 6 to 5...

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Section: Discussionmentioning

confidence: 99%

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Gellibolian

Bacolla

Wells

1997

Journal of Biological Chemistry

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“…1). The DNA ahead of the moving polymerase becomes overwound (or positively supercoiled), while the DNA in the wake of the polymerase becomes underwound, or negatively supercoiled (Chong et al 2014;Higgins 2014;Rahmouni and Wells 1992;Wu et al 1988). Unless these zones of differentially supercoiled DNA are relaxed, the polymerase can become jammed on its DNA template ).…”

Section: Dna Supercoiling and Transcriptionmentioning

confidence: 99%

DNA supercoiling is a fundamental regulatory principle in the control of bacterial gene expression

Dorman

2016

Biophys Rev

108

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Although it has become routine to consider DNA in terms of its role as a carrier of genetic information, it is also an important contributor to the control of gene expression. This regulatory principle arises from its structural properties. DNA is maintained in an underwound state in most bacterial cells and this has important implications both for DNA storage in the nucleoid and for the expression of genetic information. Underwinding of the DNA through reduction in its linking number potentially imparts energy to the duplex that is available to drive DNA transactions, such as transcription, replication and recombination. The topological state of DNA also influences its affinity for some DNA binding proteins, especially in DNA sequences that have a high A + T base content. The underwinding of DNA by the ATP-dependent topoisomerase DNA gyrase creates a continuum between metabolic flux, DNA topology and gene expression that underpins the global response of the genome to changes in the intracellular and external environments. These connections describe a fundamental and generalised mechanism affecting global gene expression that underlies the specific control of transcription operating through conventional transcription factors. This mechanism also provides a basal level of control for genes acquired by horizontal DNA transfer, assisting microbial evolution, including the evolution of pathogenic bacteria.

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“…The RNA polymerase complex is too large to follow the individual helical turns of DNA. Its movement along the template strand, therefore, transiently generates domains of positive and negative supercoiling, respectively, ahead and behind the transcriptional bubble [Wu et al, 1988;Rahmouni and Wells, 1992;Moulin et al, 2005]. These topological changes are significantly stabilized if the transcript encodes a membrane protein [Liu and Wang, 1987;Lodge et al, 1989;Lynch and Wang, 1993], because transcription and co-transcriptional translation are coupled with the insertion of nascent polypeptides into the membrane in bacteria, thereby tethering RNA polymerase to the site of protein translocation [Binenbaum et al, 1999].…”

Section: Mechansims Of Nucleoid Organizationmentioning

confidence: 99%

The bacterial nucleoid: A highly organized and dynamic structure

Thanbichler

Wang

Shapiro

2005

J of Cellular Biochemistry

122

101

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Recent advances in bacterial cell biology have revealed unanticipated structural and functional complexity, reminiscent of eukaryotic cells. Particular progress has been made in understanding the structure, replication, and segregation of the bacterial chromosome. It emerged that multiple mechanisms cooperate to establish a dynamic assembly of supercoiled domains, which are stacked in consecutive order to adopt a defined higher-level organization. The position of genetic loci on the chromosome is thereby linearly correlated with their position in the cell. SMC complexes and histone-like proteins continuously remodel the nucleoid to reconcile chromatin compaction with DNA replication and gene regulation. Moreover, active transport processes ensure the efficient segregation of sister chromosomes and the faithful restoration of nucleoid organization while DNA replication and condensation are in progress.

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Direct evidence for the effect of transcription on local DNA supercoiling in vivo

Cited by 148 publications

References 40 publications

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

Triplet Repeat Instability and DNA Topology: An Expansion Model Based on Statistical Mechanics

DNA supercoiling is a fundamental regulatory principle in the control of bacterial gene expression

The bacterial nucleoid: A highly organized and dynamic structure

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