Unlocking the role of lncREST RNA in DNA replication and repair

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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 signalling 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 localises to chromatin (the structure in which DNA is organised in the cell). Its main function is to facilitate the localisation 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 signalling, leading to the accumulation of severe DNA defects and, ultimately, cell death", explains Luisa Statello PhD, first and co-corresponding author of the study.

We have discovered that lncREST - controlled by the tumour 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."

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 cell division. In addition, it could open up a new avenue for studies to develop new therapies against cancer cells, or improve existing ones, using lncREST as a therapeutic target," argues Statello.

The researchers, who carried out the study in colorectal cancer cells and in mouse tumour 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 combination therapy to use fewer drugs and reduce toxicity to the patient. By using two inhibitors at the same time, the chances of tumour cells developing resistance to treatment are reduced," suggests Huarte.

New cutting-edge method

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 stress conditions," reveals Luisa Statello.

This research was carried out by a team of scientists with public and private funding from the Worldwide Cancer Research Foundation, the Spanish State Research Agency, the Spanish Ministry of Science, Innovation and Universities, the European Research Council (ERC) and a Marie Skłodowska Curie European grant.

Source:
Journal reference:

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

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