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Researchers discover an RNA molecule that could be used as a therapeutic target against cancer cells

Discovered a RNA molecule that helps prevent DNA replication errors
Replication stress induces lncRNAs associated to replicating chromatin. a (Top) Mechanism of action of hydroxyurea (HU) RNR: ribonucleotide reductase. (Bottom) Immunoblot analysis HCT116 cells treated with HU 1 mM for 8 h followed by 3 h recovery shows the reversible effect of HU on replication stress markers p-ATR, p-p53 and γH2A.X. Experiments were performed twice with similar results. Source data are provided as a Source Data file. b Schematic of the fractionation protocol applied to isolate chromatin-associated RNAs. c Volcano plot showing the -log10(adjusted p-value) and the log2(fold-change) from the RNA-seq differential expression analysis, comparing the HU-treated vs untreated chromatin fractions. Transcripts with ± 1logFC (FDR < 0.05) are highlighted in blue (-1logFC) and red ( + 1logFC). DESeq254 two-sided, with Benjamini-Hochberg FDR correction, was used to measure differential expression. Volcano plot was drawn using ggplot2 R package. d Distribution of the log2(fold-change) of the HU-upregulated genes in the different cell cycle stages of a synchronized RNA-seq. Data points represent the log2-ratio of the number of genes in each replication phase vs the number obtained in the 100 random sets generated. (mean ±2 x standard deviation). Source data are provided as a Source Data file e Temporal expression pattern analysis of the induced lncRNAs in RNA-seq data of cells synchronized in the different phases of the cell cycle. n = 3 (one sample Wilcoxon test, no multiple testing corrections). Fold-change is defined as the ratio between the expression in one-a time point versus the expression in the pool of all the other points. Boxplots represent 25 to 75 percentiles, and whiskers are 1.5 x interquartile range (interquartile range = percentile75-percentile25). f Enrichr analysis of the promoters of the differentially expressed genes upon HU treatment, searching against the CHEA Transcription Factor Targets database. g Overlap between the promoter of the upregulated lncRNAs and the binding sites of stress-related transcription factors. The blue squares on the grid show the candidate lncRNAs that have a binding site in their promoter for the given transcription factor. Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-45183-5

Researchers at Cima Universidad de Navarra have discovered that a ribonucleic acid that does not contain information to make proteins (long non-coding RNA) plays a crucial role in signaling and repairing errors in DNA replication during cell division. This finding could lead to the development of new anti-tumor therapies.

Scientists have identified an RNA that they named "lncREST" (long non-coding RNA REplication STress) and uncovered its role in triggering an effective response to the stress induced by rapid cell division.

"LncREST localizes to chromatin (the structure in which DNA is organized in the cell). Its main function is to facilitate the localization of key proteins in the process of DNA replication and DNA damage repair where they are needed. In fact, the absence of lncREST has been shown to cause impaired stress signaling, leading to the accumulation of severe DNA defects and, ultimately, ," explains Luisa Statello Ph.D., first and co-corresponding author of the study.

"We have discovered that lncREST—controlled by the tumor suppressor p53—acts as a functional sensor. It ensures that the necessary proteins are in the right place at the right time and, that genome replication does not fail," says Maite Huarte, leader of the study and principal investigator of the Non-Coding RNA and Cancer Genome Group at Cima Universidad de Navarra.

The work, published in the journal Nature Communications, has not only revealed IncREST as a critical component of the stress response but could also be an effective therapeutic target in the fight against various types of cancer.

"This discovery is an important step towards a better understanding of how our cells deal with stress during . In addition, it could open up a new avenue for studies to develop new therapies against , or improve existing ones, using lncREST as a therapeutic target," says Statello.

The researchers, who carried out the study in colorectal cancer cells and in mouse tumor models, also highlight the promising scenario that may result from combining known inhibitors with lncREST inhibitors to achieve a greater therapeutic effect. "The findings may lead to a to use fewer drugs and reduce toxicity to the patient. By using two inhibitors at the same time, the chances of tumor cells developing resistance to treatment are reduced," suggests Huarte.

In this study, the Cima researchers have reformulated an existing technology to detect RNA molecules in the replication process. "We have developed a methodology called iROND, which allows us to identify RNAs that are located specifically at the sites where DNA is replicating. In fact, that is how we detected lncREST associated with replication sites under conditions," says Luisa Statello.

More information: Luisa Statello et al, The chromatin-associated lncREST ensures effective replication stress response by promoting the assembly of fork signaling factors, Nature Communications (2024). DOI: 10.1038/s41467-024-45183-5

Journal information: Nature Communications
Provided by Centro de Investigación Médica Aplicada (CIMA) Universidad de Navarra
Citation: Researchers discover an RNA molecule that could be used as a therapeutic target against cancer cells (2024, March 4) retrieved 12 April 2024 from
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