Related Experiment Video

Updated: Sep 7, 2025

Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence
06:25

Quantifying Replication Stress in Ovarian Cancer Cells Using Single-Stranded DNA Immunofluorescence

Published on: February 10, 2023

2.2K

Olaparib Induces RPL5/RPL11-Dependent p53 Activation via Nucleolar Stress

Tao Han1, Jing Tong2,3, Mengxin Wang1

  • 1School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.

Frontiers in Oncology
|June 20, 2022
PubMed

Insights

Olaparib, a PARP inhibitor, activates p53 by triggering nucleolar stress and inhibiting rRNA synthesis. This pathway suppresses cancer cell survival, revealing rRNA biogenesis as a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Olaparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) used for solid tumors with homologous recombination deficiency (HRD).
  • PARPi's anti-tumor effects are linked to inhibiting DNA repair, leading to double-strand breaks (DSB) in HRD cells.
  • The precise mechanism of PARPi-induced p53-dependent cell death is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying Olaparib's induction of p53.
  • To investigate the role of nucleolar stress and rRNA biogenesis in Olaparib's anti-cancer activity.

Main Methods:

  • Treatment of cancer cells with Olaparib.
  • Assessment of p53 stabilization and downstream gene activation.
  • Analysis of nucleolar stress markers, including ribosomal RNA (rRNA) precursor (pre-rRNA) biosynthesis.
  • Investigation of interactions between ribosomal proteins (RPs), RPL5, RPL11, and MDM2.
  • Gene knockdown experiments for RPL5 and RPL11.

Main Results:

  • Olaparib treatment dose- and time-dependently stabilizes p53 and activates its target genes.
  • Olaparib induces nucleolar stress by inhibiting pre-rRNA biosynthesis.
  • Inhibition of pre-rRNA leads to increased RPL5/RPL11 interaction with MDM2, promoting p53 activation.
  • Knockdown of RPL5 and RPL11 abrogates Olaparib-induced p53 activation.
  • Olaparib suppresses breast and colorectal cancer cell proliferation via p53 activation.

Conclusions:

  • Olaparib activates a nucleolar stress-RPs-p53 pathway.
  • rRNA biogenesis is identified as a novel target for PARP inhibitors.
  • This study provides new insights into the mechanism of action for Olaparib and PARPi therapies.
Keywords:
MDM2PARP inhibitiornucleolar (ribosomal) stressp53ribosomal protein (RP)

More Related Videos

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage10:44

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

Published on: January 31, 2018

10.4K
Laser Micro-Irradiation to Study DNA Recruitment During S Phase07:11

Laser Micro-Irradiation to Study DNA Recruitment During S Phase

Published on: April 16, 2021

4.4K

Related Concept Videos

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...
9.3K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
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,...
5.9K
Negative Regulator Molecules01:23

Negative Regulator Molecules

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.
35.9K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

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...
6.8K
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...
36.7K