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Related Concept Videos

Chromosome Replication02:31

Chromosome Replication

Before a cell can divide, it must accurately replicate all of its chromosomes, including the DNA and its associated histone and non-histone proteins.  This process begins at numerous origins of replication during the S phase of the cell cycle in each of a cell’s chromosomes simultaneously. Certain nucleotides can act as origins of replication, but these sequences are not well defined - especially in complex, multi-cellular, eukaryotic species. The length of DNA that spans an origin of...
S-Cdk Initiates DNA Replication02:38

S-Cdk Initiates DNA Replication

The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of replication.
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

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, a...
Replication in Eukaryotes01:29

Replication in Eukaryotes

In eukaryotic cells, DNA replication is highly conserved and tightly regulated. Multiple linear chromosomes must be duplicated with high fidelity before cell division, so there are many proteins that fulfill specialized roles in the replication process. Replication occurs in three phases: initiation, elongation, and termination, and ends with two complete sets of chromosomes in the nucleus.
Many Proteins Orchestrate Replication at the Origin
Eukaryotic replication follows many of the same...
The DNA Replication Fork01:02

The DNA Replication Fork

An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork.   Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication forks, one in...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...

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Related Experiment Video

Updated: Jun 21, 2026

Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency
18:10

Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency

Published on: June 16, 2011

Replication origin firing capacity indicates ATR inhibitor sensitivity.

A Lumeau1, P L Pfuderer2,3, J A Scarth1

  • 1Centre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.

Nature Communications
|June 19, 2026
PubMed
Summary

Sensitivity to ATR inhibitors (ATRi) depends on DNA replication origin firing rates. High expression of replication initiation factors predicts ATRi sensitivity, aiding biomarker development for cancer patients.

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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

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Last Updated: Jun 21, 2026

Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency
18:10

Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency

Published on: June 16, 2011

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • ATR inhibitors (ATRi) are in clinical trials for cancer treatment.
  • Mechanisms of ATRi sensitivity and patient stratification biomarkers are currently lacking.

Purpose of the Study:

  • To investigate the mechanisms of ATR inhibitor sensitivity.
  • To identify biomarkers for patient stratification in ATRi therapy.

Main Methods:

  • Parallel proteomics, transcriptomics, and functional analyses were performed.
  • DNA replication origin firing rates were modulated using CDC7 inhibition, CDK2 inhibition, and CDC45 overexpression.
  • ATRi sensitivity was assessed in breast and colorectal cancer cell lines.

Main Results:

  • Sensitive cancer cell lines exhibit higher expression of DNA replication initiation factors and increased origin firing.
  • Higher origin firing rates correlated with increased pan-nuclear γH2AX signals and cell death upon ATRi treatment.
  • High expression of replication initiation factors predicted ATRi sensitivity across various cancer types and acute myeloid leukemia samples.

Conclusions:

  • Lethal origin firing capacity contributes to ATR inhibitor sensitivity.
  • Replication initiation factor expression serves as a predictive biomarker for ATRi sensitivity.
  • This study provides a foundation for developing a multimodal clinical biomarker for ATRi therapy.