Skip to main content

DNA Damage

Novel Mechanism in DNA Damage Unraveled


A research team from the University of California (UC), Irvine, has revealed a previously unknown mechanism that triggers an inflammatory immune response in cells when their DNA is damaged. The finding provides a new understanding of a new type of cell signaling that may lead to more effective treatments for cancer.

The study is published in Nature Structural & Molecular Biology in an article titled, “ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage.”

The researchers discovered that UV irradiation or certain chemotherapeutic drugs activate a specific response when cells are too damaged to be repaired correctly, preventing them from becoming cancerous.

“DNA damage in cells induces the expression of inflammatory genes,” the researchers wrote. “However, the mechanism by which cells initiate an innate immune response in the presence of DNA lesions blocking transcription remains unknown. Here we find that genotoxic stresses lead to an acute activation of the transcription factor NF-κB through two distinct pathways, each triggered by different types of DNA lesions and coordinated by either ataxia-telangiectasia mutated (ATM) or IRAK1 kinases.”

“This discovery could have significant implications for cancer treatment,” explained corresponding author Rémi Buisson, PhD, UC Irvine associate professor of biological chemistry. “Understanding how different cancer cells react to DNA damage could lead to more tailored and effective therapies, potentially reducing negative side effects and improving the quality of life for patients.”

Scientists have long understood that when both DNA strands are broken, the ATM enzyme triggers the activation of the protein NF-κB within the cell, leading to the production of inflammatory signals. In this study, spearheaded by postdoctoral fellow Elodie Bournique, PhD, and assisted by graduate student Ambrocio Sanchez, it was shown that when DNA damage occurs due to UV exposure or treatment with chemotherapeutic drugs such as actinomycin D or camptothecin, the IRAK1 enzyme induces NF-κB to send out signals to recruit immune cells.

The researchers developed an imaging technique to analyze how NF-κB is regulated at the cellular level. They were able to measure a cell’s response to damaged DNA at the single-cell level and observed a new pathway to the activation of NF-κB. They found that after specific types of injury, cells release the IL-1α protein. It doesn’t act on the cell itself but travels to neighboring cells, where it triggers the IRAK1 protein, which then initiates the NF-κB inflammatory response.

“Our findings will help us better understand the consequences of certain types of chemotherapeutic drugs that are used to treat patients and cause DNA damage. We’ve discovered that the IL-1α and IRAK1 proteins, which play a role in the immune process, vary significantly across different cancer cell types. This suggests that not all patients will react to treatment in the same way, Buisson said. “By assessing these protein levels ahead of time, doctors might be able to personalize therapies tailored to individual patients’ needs for improved success rates.”

Looking toward the future, the researchers will continue their work by testing their findings on mouse models that lack specific factors involved in the new pathway.

DNA repair, oxidative stress, genomic instability, cell cycle checkpoints, DNA double-strand breaks, single-strand breaks, DNA methylation, nucleotide excision repair, base excision repair, homologous recombination, non-homologous end joining, telomere shortening, replication stress, chromosomal aberrations, mutagenesis, apoptosis, tumorigenesis, reactive oxygen species, genetic mutations, cancer progression

#DNArepair, #GenomicInstability, #CellCycle, #DNADamage, #OxidativeStress, #ChromosomalAberrations, #Mutagenesis, #Telomeres, #HomologousRecombination, #NonHomologousEndJoining, #BaseExcisionRepair, #NucleotideExcisionRepair, #ReactiveOxygenSpecies, #ReplicationStress, #Tumorigenesis, #DNARepairMechanisms, #CancerResearch, #GeneticMutations, #Apoptosis, #GenomeIntegrity

Comments

Popular posts from this blog

Fruitful innovation

Fruitful innovation: Transforming watermelon genetics with advanced base editors The development of new adenine base editors (ABE) and adenine-to-thymine/ guanine base editors (AKBE) is transforming watermelon genetic engineering. These innovative tools enable precise A:T-to-G and A:T-to-T base substitutions, allowing for targeted genetic modifications. The research highlights the efficiency of these editors in generating specific mutations, such as a flowerless phenotype in ClFT (Y84H) mutant plants. This advancement not only enhances the understanding of gene function but also significantly improves molecular breeding, paving the way for more efficient watermelon crop improvement. Traditional breeding methods for watermelon often face challenges in achieving desired genetic traits efficiently and accurately. While CRISPR/Cas9 has provided a powerful tool for genome editing, its precision and scope are sometimes limited. These limitations highlight the need for more advanced gene-e...

Genetic factors with clinical trial stoppage

Genetic factors associated with reasons for clinical trial stoppage Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to ...

Genetics study on COVID-19

Large genetic study on severe COVID-19 Bonn researchers confirm three other genes for increased risk in addition to the known TLR7 gene Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in cooperation with other research teams from Germany, the Netherlands, Spain and Italy, investigated a particularly large group of affected individuals. They confirmed the central and already known role of the TLR7 gene in severe courses of the disease in men, but were also able to find evidence for a contribution of the gene in women. In addition, they were able to show that genetic changes in three other genes of the innate immune system contribute to severe COVID-19. The results have now been published in the journal " Human Genetics and Genomics Advances ". Even though the number of severe cases following infection with the SARS-CoV-...