Synergistic Coordination of Chromatin Torsional Mechanics and Topoisomerase Activity

Le, Tung T.; Gao, Xiang; Park, Seong ha; Lee, Jaeyoon; Inman, James T.; Lee, Joyce H.; Badman, Ryan P.; Wang, Michelle D.

doi:10.1016/j.cell.2019.09.034

Cited by 64 publications

(101 citation statements)

References 98 publications

(136 reference statements)

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“…As for the possibilities to use DNA fibers to test our hypothesis, it was recently demonstrated that a single chromatin fiber is torsionally softer than a braided one by direct torque measurements. 64 Since SMF directly interferes with torsional mechanics of DNA, experiments with DNA fibers will not help to test our hypothesis. Moreover, in a single oriented molecule experiment, there are no reasons for DNA rotation and replication under intrinsic forces because it is not a living system.…”

Section: Discussionmentioning

confidence: 99%

Effect of static magnetic field on DNA synthesis: The interplay between DNA chirality and magnetic field left‐right asymmetry

Yang

Polyakova

et al. 2020

FASEB BioAdvances

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Interactions between magnetic fields (MFs) and living cells may stimulate a large variety of cellular responses to a MF, while the underlying intracellular mechanisms still remain a great puzzle. On a fundamental level, the MF — cell interaction is affected by the two broken symmetries: (a) left‐right (LR) asymmetry of the MF and (b) chirality of DNA molecules carrying electric charges and subjected to the Lorentz force when moving in a MF. Here we report on the chirality‐driven effect of static magnetic fields (SMFs) on DNA synthesis. This newly discovered effect reveals how the interplay between two fundamental features of symmetry in living and inanimate nature—DNA chirality and the inherent features of MFs to distinguish the left and right—manifests itself in different DNA synthesis rates in the upward and downward SMFs, consequently resulting in unequal cell proliferation for the two directions of the field. The interplay between DNA chirality and MF LR asymmetry will provide fundamental knowledge for many MF‐induced biological phenotypes.

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Section: Discussionmentioning

confidence: 99%

Effect of static magnetic field on DNA synthesis: The interplay between DNA chirality and magnetic field left‐right asymmetry

Yang

Polyakova

et al. 2020

FASEB BioAdvances

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“…It is conceivable that in csm3Δ, tof1Δ, and tof1-ΔC strains topoisomerases I and II do eventually relieve torsional stress in front of the fork (either independently or as part of multiprotein complexes), but perhaps only after the torsion has reached higher levels. Of note, Top2 was recently shown in vitro to strongly favor a single chromatin fiber over two independent fibers as a substrate (Le et al 2019), a preference that would support its general activity ahead of the fork irrespective of replisome composition. Our findings indicate that either Top1 or Top2 is able to impose replication fork pausing at the Fob1-RFB, through a mechanism that we dub "sTOP" ("slowing down with topoisomerase I and II") ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Fork pausing complex engages topoisomerases at the replisome

et al. 2019

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Replication forks temporarily or terminally pause at hundreds of hard-to-replicate regions around the genome. A conserved pair of budding yeast replisome components Tof1-Csm3 (fission yeast Swi1-Swi3 and human TIMELESS -TIPIN) act as a "molecular brake" and promote fork slowdown at proteinaceous replication fork barriers (RFBs), while the accessory helicase Rrm3 assists the replisome in removing protein obstacles. Here we show that the Tof1-Csm3 complex promotes fork pausing independently of Rrm3 helicase by recruiting topoisomerase I (Top1) to the replisome. Topoisomerase II (Top2) partially compensates for the pausing decrease in cells when Top1 is lost from the replisome. The C terminus of Tof1 is specifically required for Top1 recruitment to the replisome and fork pausing but not for DNA replication checkpoint (DRC) activation. We propose that forks pause at proteinaceous RFBs through a "sTOP" mechanism ("slowing down with topoisomerases I-II"), which we show also contributes to protecting cells from topoisomerase-blocking agents.

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“…Moreover, it remains unclear how Top2 is recruited to the replisome, for example through as yet unknown protein-protein interactions or DNA topology. Recruitment of Top2 ahead of the fork may be favored by its biophysical preference for a single parental chromatid (Le et al, 2019).…”

Section: Dna Topology Topoisomerases and Replisome Pausingmentioning

confidence: 99%

Approaching Protein Barriers: Emerging Mechanisms of Replication Pausing in Eukaryotes

Shyian

Shore

2021

Front. Cell Dev. Biol.

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During nuclear DNA replication multiprotein replisome machines have to jointly traverse and duplicate the total length of each chromosome during each cell cycle. At certain genomic locations replisomes encounter tight DNA-protein complexes and slow down. This fork pausing is an active process involving recognition of a protein barrier by the approaching replisome via an evolutionarily conserved Fork Pausing/Protection Complex (FPC). Action of the FPC protects forks from collapse at both programmed and accidental protein barriers, thus promoting genome integrity. In addition, FPC stimulates the DNA replication checkpoint and regulates topological transitions near the replication fork. Eukaryotic cells have been proposed to employ physiological programmed fork pausing for various purposes, such as maintaining copy number at repetitive loci, precluding replication-transcription encounters, regulating kinetochore assembly, or controlling gene conversion events during mating-type switching. Here we review the growing number of approaches used to study replication pausing in vivo and in vitro as well as the characterization of additional factors recently reported to modulate fork pausing in different systems. Specifically, we focus on the positive role of topoisomerases in fork pausing. We describe a model where replisome progression is inherently cautious, which ensures general preservation of fork stability and genome integrity but can also carry out specialized functions at certain loci. Furthermore, we highlight classical and novel outstanding questions in the field and propose venues for addressing them. Given how little is known about replisome pausing at protein barriers in human cells more studies are required to address how conserved these mechanisms are.

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Synergistic Coordination of Chromatin Torsional Mechanics and Topoisomerase Activity

Cited by 64 publications

References 98 publications

Effect of static magnetic field on DNA synthesis: The interplay between DNA chirality and magnetic field left‐right asymmetry

Effect of static magnetic field on DNA synthesis: The interplay between DNA chirality and magnetic field left‐right asymmetry

Fork pausing complex engages topoisomerases at the replisome

Approaching Protein Barriers: Emerging Mechanisms of Replication Pausing in Eukaryotes

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