Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication

Ahmed, Syed Moiz; Dröge, Peter

doi:10.3390/ijms21124504

Cited by 13 publications

(11 citation statements)

References 123 publications

(151 reference statements)

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“…The nucleus, nuclear envelope and associated cytoskeleton have roles in mechanotransduction pathways that regulate cellular activity [ 96 ]. Cell nuclei are mechanosensitive organelles that allow cells to perceive and respond to mechanical stimuli [ 207 , 208 ].…”

Section: Nuclear Mechanosensory Properties: Dynamic Interplay Of Proteins In the Nucleoskeleton Nuclear Envelope And Cytoskeleton Providementioning

confidence: 99%

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

Hayes

Melrose

2021

IJMS

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The recent discovery of nuclear and perinuclear perlecan in annulus fibrosus and nucleus pulposus cells and its known matrix stabilizing properties in tissues introduces the possibility that perlecan may also have intracellular stabilizing or regulatory roles through interactions with nuclear envelope or cytoskeletal proteins or roles in nucleosomal-chromatin organization that may regulate transcriptional factors and modulate gene expression. The nucleus is a mechano-sensor organelle, and sophisticated dynamic mechanoresponsive cytoskeletal and nuclear envelope components support and protect the nucleus, allowing it to perceive and respond to mechano-stimulation. This review speculates on the potential roles of perlecan in the nucleus based on what is already known about nuclear heparan sulphate proteoglycans. Perlecan is frequently found in the nuclei of tumour cells; however, its specific role in these diseased tissues is largely unknown. The aim of this review is to highlight probable roles for this intriguing interactive regulatory proteoglycan in the nucleus of normal and malignant cell types.

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Section: Nuclear Mechanosensory Properties: Dynamic Interplay Of Proteins In the Nucleoskeleton Nuclear Envelope And Cytoskeleton Providementioning

confidence: 99%

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

Hayes

Melrose

2021

IJMS

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“…DNA in the cell is complexed with proteins and adopts a highly compact structure including protein-mediated loops and supercoiling ( 1–11 ). Genome-bound proteins can be roadblocks that hinder elongation by RNA polymerase (RNAP) during transcription ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Positive supercoiling favors transcription elongation through lac repressor-mediated DNA loops

Yan

Artsimovitch

et al. 2022

Nucleic Acids Research

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Some proteins, like the lac repressor (LacI), mediate long-range loops that alter DNA topology and create torsional barriers. During transcription, RNA polymerase generates supercoiling that may facilitate passage through such barriers. We monitored E. coli RNA polymerase progress along templates in conditions that prevented, or favored, 400 bp LacI-mediated DNA looping. Tethered particle motion measurements revealed that RNA polymerase paused longer at unlooped LacI obstacles or those barring entry to a loop than those barring exit from the loop. Enhanced dissociation of a LacI roadblock by the positive supercoiling generated ahead of a transcribing RNA polymerase within a torsion-constrained DNA loop may be responsible for this reduction in pause time. In support of this idea, RNA polymerase transcribed 6-fold more slowly through looped DNA and paused at LacI obstacles for 66% less time on positively supercoiled compared to relaxed templates, especially under increased tension (torque). Positive supercoiling propagating ahead of polymerase facilitated elongation along topologically complex, protein-coated templates.

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“…DNA in the cell is decorated by proteins and adopts a highly compacted structure which includes protein-mediated loops and supercoiling 1–11 . Genome-bound proteins can be roadblocks that hinder elongation by RNA polymerase (RNAP) during transcription 12 .…”

Section: Introductionmentioning

confidence: 99%

Positive supercoiling favors transcription elongation through lac repressor-mediated DNA loops

Xu¹,

Yan²,

Artsimovitch³

et al. 2021

Preprint

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During elongation, RNA polymerase (RNAP) must navigate through proteins that decorate genomic DNA. Several of these mediate long-distance interactions via structures, such as loops, that alter DNA topology and create torsional barriers. We used the tethered particle motion (TPM) technique and magnetic tweezers to monitor transcription of DNA templates in the presence of the lac repressor (LacI) protein which could bind at two sites, one proximal to, and one distal from, the promoter. The bivalent LacI tetramer binds recognition sites (operators) with up to nanomolar affinity depending on the sequence, and the concentration of LacI was adjusted to promote binding to either one or both operators, so as to produce unlooped or looped DNA. We observed that RNAP pausing before a LacI-securing loop was determined not by the affinity of LacI for the operator, but by the order in which the elongating RNAP encountered these operators. TPM experiments showed that, independent of affinity, LacI bound at the promoter-proximal operator became a stronger roadblock when securing a loop. In contrast, LacI bound to the distal operator was a weaker roadblock in a looped configuration suggesting that RNAP might more easily displace LacI obstacles within a torsion-constrained DNA loop. Since protein junctions can efficiently block the diffusion of DNA supercoiling, these data indicate that the positive supercoiling generated ahead of a transcribing RNAP may facilitate the dissociation of a roadblock. In support of this idea, magnetic tweezers measurements indicated that pauses are shorter when RNAP encounters obstacles on positively supercoiled than on relaxed DNA. Furthermore, at similar winding levels of the DNA template, RNAP pause duration decreased with tension. These findings are significant for our understanding of transcription within the crowded and tensed nucleoid.

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Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication

Cited by 13 publications

References 123 publications

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

Positive supercoiling favors transcription elongation through lac repressor-mediated DNA loops

Positive supercoiling favors transcription elongation through lac repressor-mediated DNA loops

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