Related Experiment Video

Updated: Jun 16, 2025

Visualization of DNA Replication in the Vertebrate Model System DT40 using the DNA Fiber Technique

Visualization of DNA Replication in the Vertebrate Model System DT40 using the DNA Fiber Technique

Published on: October 27, 2011

DNA polymerase beta expression in head & neck cancer modulates the poly(ADP-ribose)-mediated replication checkpoint

Md Maruf Khan¹, Wynand P Roos², Charlotte R Pearson²

¹Department of Pharmacology & Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA.

|June 5, 2025

Summary

In head and neck cancer, inhibiting PARG triggers cell death, but Polβ overexpression causes resistance. Combining PARG and ATR/CHK1 inhibitors overcomes this resistance, offering a new HNSCC treatment strategy.

Area of Science:

Oncology
Molecular Biology
Cancer Therapeutics

Background:

Head and Neck Squamous Cell Carcinoma (HNSCC) presents significant treatment challenges due to limited efficacy and severe side effects of current therapies.
DNA polymerase beta (Polβ) plays a critical role in DNA replication stress and cellular responses to DNA damage.
Poly(ADP-ribose) glycohydrolase (PARG) regulates poly(ADP-ribose) (PAR) levels, influencing DNA damage response pathways.

Purpose of the Study:

To investigate the role of Polβ in HNSCC response to PARG inhibitors.
To explore therapeutic strategies for overcoming Polβ-mediated resistance to PARG inhibitors in HNSCC.
To evaluate the efficacy of combining PARG inhibitors with ATR/CHK1 inhibitors.

Main Methods:

Assessed cellular responses to PARG inhibition in HNSCC cells with varying Polβ levels.
Investigated replication stress, cell cycle arrest, and apoptosis induction.
Performed in vitro experiments combining PARG inhibitors with ATR/CHK1 inhibitors.

Main Results:

PARG inhibition in HNSCC cells induced replication stress and apoptosis, but Polβ overexpression mitigated this response.
HNSCC cells overexpressing Polβ exhibited resistance to PARG inhibitor treatment.
Combination therapy of PARG and ATR/CHK1 inhibitors demonstrated synergistic effects, overcoming Polβ-mediated resistance.

Conclusions:

Polβ levels critically influence HNSCC sensitivity to PARG inhibitors.
Targeting Polβ-mediated resistance through combination therapy with PARG and ATR/CHK1 inhibitors is a promising strategy for HNSCC.
This approach offers a potential new therapeutic paradigm for improving HNSCC treatment outcomes.

Keywords:

Ancestry informative markers DNA polymerase beta HNSCC PARG Poly-ADP-ribose

More Related Videos

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

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

Published on: April 28, 2021

Strand-Specific Analysis of Proteins at Replicating DNA Strands by Enrichment and Sequencing of Protein-Associated Nascent DNA Method

Strand-Specific Analysis of Proteins at Replicating DNA Strands by Enrichment and Sequencing of Protein-Associated Nascent DNA Method

Published on: May 2, 2025

Related Concept Videos

Proofreading

Proofreading

Synthesis of new DNA molecules is carried out by the enzyme DNA polymerase, which adds nucleotides on the daughter strand complementary to the template DNA strand. DNA polymerase has a higher affinity to add the correct base and ensures fidelity during DNA replication. Furthermore, it exhibits proofreading activity during replication, using an exonuclease domain that cuts off incorrect nucleotides from the nascent DNA strand.
Errors During Replication are Corrected by the DNA Polymerase...

DNA Damage can Stall the Cell Cycle

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...

The DNA Replication Fork

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...

Restarting Stalled Replication Forks

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,...

Translesion DNA Polymerases

Translesion DNA Polymerases

Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
TLS polymerases are found in all three domains of life - archaea, bacteria, and eukaryotes. Of the different classes of TLS polymerases, members of the Y family are fitted with specialized structures that...

DNA Helicases

DNA Helicases

DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...

Articles linked to this work by shared authors, journal, and citation graph.

Ancestry informative genetic variants associated with tobacco metabolic and detoxification capacity measured by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) among smokers.

Archives of toxicology·2026

Isobonducellin phytocompound from Artemisia annua L. plant exhibits anti-colorectal cancer activity via AKT1 regulation: an in-silico study.

Computers in biology and medicine·2026

In silico screening and molecular analyses identify apigenin from Scutellaria barbata as a potent AKT1 inhibitor in breast cancer.

PloS one·2026

Establishing the first Afro-Caribbean breast cancer cell lines reveals ECM pathway enrichment and distinctive drug sensitivities.

Scientific reports·2026

Visualization and Quantitative Analysis of Genotoxin-induced PARP1/PARP2 Activation in Cells using a Fluorescent Fusion Protein-based Reporter.

Journal of visualized experiments : JoVE·2026

Ubiquitylation of DNA polymerase β via atypical K27 chains signals a DNA damage response.

Nucleic acids research·2026

See all related articles