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Related Concept Videos

The Replisome03:01

The Replisome

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DNA replication is carried out by a large complex of proteins that act in a coordinated matter to achieve high-fidelity DNA replication. Together this complex is known as the DNA replication machinery or the replisome.
The synthesis of the leading and lagging strands is a highly coordinated process. To explain this, the “Trombone model” was proposed by Bruce Alberts in 1980. The DNA loop formation starts when a primer is synthesized on the parent lagging strand. The loop grows with...
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Restarting Stalled Replication Forks02:37

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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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Homologous Recombination02:31

Homologous Recombination

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The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
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Disassembly of Intermediate Filaments01:35

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Intermediate filaments (IFs) do not undergo spontaneous disassembly. Enzymes, kinases, and phosphatases add and remove phosphates from specific sites to regulate their disassembly. The IF concentration in the cytoplasm also regulates the disassembly. If the concentration crosses a threshold, it activates the protein kinases in the vicinity, allowing the phosphorylation of IFs.
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Replicative Cell Senescence02:15

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Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds...
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Nucleosome Remodeling02:54

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Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
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Related Experiment Video

Updated: Jun 19, 2025

Author Spotlight: Investigating the Motion Dynamics of the Eukaryotic Replisome Components at the Single-Molecule Level
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Author Spotlight: Investigating the Motion Dynamics of the Eukaryotic Replisome Components at the Single-Molecule Level

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Characterizing replisome disassembly in human cells.

Rebecca M Jones1, Joaquin Herrero Ruiz1,2, Shaun Scaramuzza1

  • 1Institute of Cancer and Genomic Sciences, Birmingham Centre for Genome Biology, University of Birmingham, Birmingham, UK.

Iscience
|July 26, 2024
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Summary

Replisome unloading in human cells requires MCM7 ubiquitylation and p97/VCP segregase, with evidence for conserved backup mechanisms. Inhibitors show limited use due to replication stress induction.

Keywords:
biochemistrycell biologygenetics

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA replication requires timely genome duplication by thousands of replisomes during S phase.
  • Replisome unloading from chromatin is a critical final step in DNA replication.
  • Mechanisms of replication termination and replisome disassembly are well-studied in model organisms but less understood in human somatic cells.

Purpose of the Study:

  • To investigate the molecular mechanisms and regulation of replisome disassembly in human somatic cells.
  • To identify key proteins and pathways involved in MCM7 ubiquitylation and replisome unloading.
  • To explore the conservation of replisome disassembly mechanisms, including potential backup pathways.

Main Methods:

  • Utilized human somatic cell systems to study replisome unloading.
  • Investigated the roles of CUL2LRR1, p97/VCP, and UBXN7 in MCM7 ubiquitylation and replisome disassembly.
  • Assessed the effects of Cullin ubiquitin ligase inhibitors (CULi) and p97 inhibitors (p97i) on replisome unloading and replication stress.

Main Results:

  • Demonstrated that CUL2LRR1-driven MCM7 ubiquitylation and p97/VCP segregase are essential for replisome unloading in human cells.
  • Provided evidence for a conserved "backup" mitotic replisome disassembly pathway.
  • Showed that CULi and p97i inhibit replisome unloading but also induce replication stress, limiting their specific therapeutic application.

Conclusions:

  • Replisome disassembly in human somatic cells relies on a conserved ubiquitylation-segregase pathway involving MCM7, CUL2LRR1, and p97/VCP.
  • The identification of backup disassembly mechanisms highlights the robustness of genome maintenance.
  • Small-molecule inhibitors targeting this pathway have dual effects, impacting both disassembly and inducing replication stress, thus requiring careful consideration for therapeutic development.