Related Experiment Video

Updated: Aug 21, 2026

In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing
10:44

In Vitro Selection of Engineered Transcriptional Repressors for Targeted Epigenetic Silencing

Published on: May 5, 2023

Targeting epigenetic regulators induces transcription-replication conflicts to overcome ATR inhibitor resistance

Samah W Awwad1,2, Holly Barber1,3, Josie Coulthard1

  • 1Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom.

Nucleic Acids Research
|August 20, 2026
PubMed

Insights

Targeting epigenetic regulators like HDAC3 or PRC2 can restore sensitivity to ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors (ATRi) in resistant cancers. This approach induces transcriptional dysregulation and replication stress, offering a new strategy against ATRi resistance.

Area of Science:

  • Cancer Biology
  • Epigenetics
  • Genomic Stability

Background:

  • Cancer cells rely on ATR kinase for survival amid replication stress.
  • Resistance to ATR inhibitors (ATRi) is a major therapeutic challenge.
  • Loss of CDK8/CCNC subunits confers ATRi resistance by reducing transcription-dependent replication stress.

Purpose of the Study:

  • Identify vulnerabilities to restore ATRi sensitivity in resistant cancer cells.
  • Explore the role of epigenetic regulators in ATRi resistance.
  • Validate therapeutic strategies targeting epigenetic pathways.

Main Methods:

  • Genome-wide CRISPR screens in wild-type and CDK8-deficient cells.
  • Assessing ATRi sensitivity upon impairment of epigenetic components.
  • In vivo tumor growth studies following HDAC3 loss.
  • Pharmacological inhibition of HDAC3 and PRC2.

Main Results:

  • Impairment of HDAC3 or PRC2 enhances ATRi sensitivity, especially in CDK8/CCNC-deficient cells.
  • This sensitivity is driven by transcriptional dysregulation, increased transcription-replication collisions, and replication stress.
  • HDAC3 loss significantly limits the growth of ATRi-resistant tumors in vivo.
  • Pharmacological inhibition of HDAC3/PRC2 mimics genetic loss effects.

Conclusions:

  • Targeting epigenetic regulators like HDAC3 and PRC2 is a promising strategy to overcome ATRi resistance.
  • Inducing transcriptional dysregulation and replication stress can re-sensitize resistant cancers to ATRi.
  • Pharmacological targeting of epigenetic pathways offers a viable therapeutic approach for ATRi-resistant cancers.

More Related Videos

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers10:28

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Published on: September 20, 2018

Related Concept Videos

Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...
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...
Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...