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Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

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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...
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Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Long-patch Base Excision Repair01:02

Long-patch Base Excision Repair

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Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
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Negative Regulator Molecules01:23

Negative Regulator Molecules

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Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
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Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

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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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The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

6.4K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Atr Inhibition Increases Reliance On Parp-mediated Dna Repair Revealing An Improved Therapeutic Strategy For Cervical Cancer.
  1. Home
  3. Research Domains
  5. Biomedical And Clinical Sciences
  7. Oncology And Carcinogenesis
  9. Predictive And Prognostic Markers
  11. Atr Inhibition Increases Reliance On Parp-mediated Dna Repair Revealing An Improved Therapeutic Strategy For Cervical Cancer.

Related Experiment Video

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
06:44

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging

Published on: April 28, 2021

3.9K

ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer.

Sugantha Priya Elayapillai1, Samrita Dogra1, James Lausen2

  • 1Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Gynecologic Oncology
|October 20, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

The study found that combining an ATR inhibitor with a PARP inhibitor can induce synthetic lethality in cervical cancer cells, leading to reduced tumor growth. This combination therapy shows promise for treating high-risk human papillomavirus-positive cervical cancer.

Keywords:
ATRCervical cancerDNA damage repairHPV-related cancer

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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays

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Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage
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Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage

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Related Experiment Videos

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging
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Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging

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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
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Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays

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Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage
10:44

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage

Published on: January 31, 2018

10.2K

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Cervical cancer is driven by high-risk human papillomavirus (HR-HPV) oncoproteins E6 and E7.
  • These oncoproteins disrupt cell cycle checkpoints and DNA damage repair (DDR) pathways, increasing reliance on ATR and PARP.
  • Targeting these DDR pathways presents a potential therapeutic strategy for cervical cancer.

Purpose of the Study:

  • To investigate the effects of an ATR inhibitor (ATRi) and a PARP inhibitor (PARPi) on HR-HPV+ cervical cancer.
  • To evaluate the efficacy of ATRi and PARPi as monotherapy and in combination.
  • To assess the impact on cell viability, cell cycle, apoptosis, and DDR pathways in vitro and in vivo.

Main Methods:

  • In vitro studies using cervical cancer cell lines treated with ATRi (AZD6738) and PARPi (AZD2281) alone and in combination.
PARP
  • Evaluation of metabolic viability, cell cycle arrest, apoptosis, and DNA damage response.
  • In vivo assessment using a cervical cancer xenograft model.

    • Main Results:

    • Both ATRi and PARPi demonstrated sensitivity as monotherapies.
    • Combination therapy showed synergy in reducing metabolic viability when ATRi preceded PARPi, due to ATRi-induced PARP upregulation.
    • The combination induced G2 cell cycle arrest and apoptosis, enhanced DNA damage, and inhibited homologous recombination repair.
    • ATRi significantly reduced tumor growth in xenografts, irrespective of concurrent PARPi treatment at studied doses.

    Conclusions:

    • ATRi enhances dependency on PARP for metabolic viability in cervical cancer cells.
    • Combined ATRi and PARPi treatment resulted in synthetic lethality in vitro.
    • This combination therapy demonstrated a reduction in tumor burden in vivo, indicating therapeutic potential.