Related Experiment Video

Updated: Dec 1, 2025

Techniques to Induce and Quantify Cellular Senescence

Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

Benzo[a]pyrene represses DNA repair through altered E2F1/E2F4 function marking an early event in DNA damage-induced

Sebastian Allmann¹, Laura Mayer¹, Jessika Olma¹

¹Institute of Toxicology, University Medical Center, Johannes Gutenberg University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.

Nucleic Acids Research

|November 9, 2020

Abstract:

Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.

Insights

Environmental carcinogen benzo[a]pyrene (B[a]P) represses DNA repair genes, including mismatch repair (MMR) and homologous recombination (HR) pathways. This downregulation, linked to cellular senescence, may maintain the senescent state by allowing DNA damage accumulation.

Area of Science:

Molecular Biology
Genetics
Cell Biology

Background:

Transcriptional regulation of DNA repair is crucial for maintaining genomic integrity under genotoxic stress.
Environmental carcinogens can disrupt normal cellular processes, including DNA repair mechanisms.

Purpose of the Study:

To investigate the effect of benzo[a]pyrene (B[a]P) on DNA repair gene expression.
To elucidate the molecular mechanisms underlying B[a]P-induced DNA repair downregulation.
To determine if this repression is linked to cellular senescence.

Main Methods:

Analysis of mismatch repair (MMR) and homologous recombination (HR) gene expression.
Investigation of E2F1 signaling pathways and the p21-dependent E2F4/DREAM complex.
Cell cycle analysis and assessment of senescence markers following B[a]P exposure.

Main Results:

B[a]P treatment leads to transcriptional repression of MMR genes (MSH2, MSH6, EXO1) and RAD51.
E2F1 signaling is abrogated via proteasomal degradation (G2) or mRNA downregulation (G1), mediated by the p21-dependent E2F4/DREAM complex.
Repression of DNA repair is observed with B[a]P metabolites and ionizing radiation, coinciding with p53/p21-triggered senescence.

Conclusions:

Downregulation of MMR and HR is an early event in genotoxic stress-induced senescence.
Persistent suppression of DNA repair may contribute to maintaining the senescence phenotype.
Accumulation of unrepaired DNA lesions could be a consequence of this repair deficiency in senescent cells.

Read full analysis

More Related Videos

Induction and Validation of Cellular Senescence in Primary Human Cells

Induction and Validation of Cellular Senescence in Primary Human Cells

Published on: June 20, 2018

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

A Quantitative Measurement of Reactive Oxygen Species and Senescence-associated Secretory Phenotype in Normal Human Fibroblasts During Oncogene-induced Senescence

Published on: August 12, 2018

Related Concept Videos

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...

DNA Damage Can Stall the Cell Cycle

DNA Damage Can Stall the Cell Cycle

Overview of DNA Repair

Overview of DNA Repair

In order to be passed through generations, genomic DNA must be undamaged and error-free. However, every day, DNA in a cell undergoes several thousand to a million damaging events by natural causes and external factors. Ionizing radiation such as UV rays, free radicals produced during cellular respiration, and hydrolytic damage from metabolic reactions can alter the structure of DNA. Damages caused include single-base alteration, base dimerization, chain breaks, and cross-linkage.
Chemically...

Overview of DNA Repair

Overview of DNA Repair

Negative Regulator Molecules

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.

Abnormal Proliferation

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...

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

Nocturnal Cerebral Oxygenation in Low-Altitude Residents With Pulmonary Vascular Disease Staying Overnight at High Altitude. Data From a Randomized, Controlled, Crossover Trial.

Pulmonary circulation·2026

Iron Homeostasis at High Altitude in Patients With Pulmonary Hypertension.

Pulmonary circulation·2026

Effect of sildenafil on resting and exercise haemodynamics in hypoxia in patients with pulmonary vascular diseases: data from a randomised controlled trial.

ERJ open research·2026

The Effect of a 2-Day Stay at High Altitude (2,500 m) on Right Ventricular Afterload and Oxygen Delivery in Patients With Pulmonary Vascular Disease: A Randomized Controlled Crossover Trial.

Chest·2026

The effect of high altitude on exercise capacity and cardiorespiratory function in patients with pulmonary vascular disease after an overnight stay at 2500 m: a randomised crossover study.

ERJ open research·2026

Pancreatic cancer induces B cell lineage plasticity via Pax5 inhibition to sustain immunosuppression.

Cell death discovery·2026

See all related articles