Related Experiment Video

Updated: Jul 20, 2025

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
07:23

Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

Published on: May 30, 2025

454

Small molecule targeting of transcription-replication conflict for selective chemotherapy

Long Gu1, Min Li2, Caroline M Li1

  • 1Department of Molecular Diagnostics & Experimental Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.

Cell Chemical Biology
|August 2, 2023
PubMed

Insights

A novel small molecule, AOH1996, targets transcription-replication conflicts by inhibiting proliferating cell nuclear antigen (PCNA), selectively killing cancer cells with minimal side effects.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Genomics

Background:

  • Transcription-replication conflicts are a significant source of DNA damage and genomic instability in cancer.
  • Proliferating cell nuclear antigen (PCNA) plays a crucial role in DNA replication and repair.
  • Targeting these conflicts presents a potential anticancer therapeutic strategy.

Purpose of the Study:

  • To identify and characterize a novel small molecule inhibitor of PCNA.
  • To investigate the mechanism of action of AOH1996 in cancer cells.
  • To evaluate the therapeutic potential of AOH1996 in preclinical cancer models.

Main Methods:

  • Rational drug design was employed to identify AOH1996, a PCNA inhibitor.
  • The study examined the interaction between PCNA and RNA polymerase II subunit RPB1.
  • Cancer cell lines and tumor models were used to assess AOH1996's efficacy and safety.

Main Results:

  • AOH1996 selectively induces cancer cell death by enhancing PCNA-RPB1 interaction and dissociating PCNA from transcribed chromatin.
  • This leads to transcription-dependent DNA double-strand breaks.
  • A point mutation in RPB1's PCNA-binding region conferred resistance to AOH1996.
  • AOH1996 demonstrated tumor growth suppression as a monotherapy or combination treatment with no significant side effects.

Conclusions:

  • AOH1996 is an orally administrable and metabolically stable PCNA inhibitor with anticancer activity.
  • Targeting transcription-replication conflicts represents a promising therapeutic avenue for cancer treatment.
  • AOH1996 exploits a cancer-selective vulnerability with potential for broad application.
Keywords:
DNA repairDNA replication stressPCNAtranscription-replication conflict

More Related Videos

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors06:07

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

Published on: August 5, 2022

2.6K
An In Vitro Enzymatic Assay to Measure Transcription Inhibition by GalliumIII and H3 5,10,15-trispentafluorophenylcorroles09:00

An In Vitro Enzymatic Assay to Measure Transcription Inhibition by GalliumIII and H3 5,10,15-trispentafluorophenylcorroles

Published on: March 18, 2015

11.6K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.7K
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...
3.3K
DNA Damage can Stall the Cell Cycle02:37

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...
9.2K
DNA Helicases00:55

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...
21.5K
Conservative Site-specific Recombination and Phase Variation02:53

Conservative Site-specific Recombination and Phase Variation

Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
6.0K
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,...
5.8K