Our DNA is constantly under threat — from cell division errors to external factors like sunlight and smoking. Fortunately, cells have intricate repair mechanisms to counteract this damage.
Scientists have uncovered a surprising role played by long non-coding RNA, particularly NEAT1, in stabilizing the genome. Their findings suggest that NEAT1, when highly methylated, helps the cell recognize and repair broken DNA strands more efficiently. This discovery could pave the way for new cancer treatments targeting tumors with high NEAT1 expression.
Genome Instability and Disease Risk
Every time a cell divides, its DNA is at risk of damage. To complete division, the cell must copy its entire genetic code — billions of letters long — which can lead to occasional errors. But cell division isn't the only threat. Over time, exposure to factors like sunlight, alcohol, and cigarette smoke can also harm DNA, increasing the risk of cancer and other diseases.
Fortunately, cells have built-in repair systems to counteract this damage. This process, known as the DNA damage response (DDR), activates specific signaling pathways that detect and fix errors. These mechanisms help maintain genetic stability and ensure the cell's survival.
A New Look at the DNA Damage Response
A team of scientists from Julius-Maximilians-Universität Würzburg (JMU) in Bavaria, Germany, has now taken a closer look at one of these signaling pathways. The group has identified a new mechanism of the DNA damage response that is mediated via an RNA transcript. Their results help to broaden the conceptual view on the DNA damage response and to link it more closely with RNA metabolism.
Dr. Kaspar Burger, junior research group leader at the Department of Biochemistry and Molecular Biology, was responsible for this study. The group has published the results of their investigations in the journal Genes & Development.
RNA Transcripts as Key Regulators
"In our study, we focused on so-called long non-coding RNA transcripts. Previous data suggest that some of these transcripts act as regulators of genome stability," says Kaspar Burger, explaining the background to the work. The study focused on the nuclear enriched abundant transcript 1 — also known as NEAT1 — which is found in high concentrations in many tumor cells. NEAT1 is also known to react to DNA damage and to cellular stress. However, its exact role in the DNA damage response was previously unclear.
"Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response in order to ensure the stability of the genome," says Burger. To test this hypothesis, the research group experimentally investigated how NEAT1 reacts to serious damage to the genome — so-called DNA double-strand breaks — in human bone cancer cells. The result: "We were able to show that DNA double-strand breaks increase both the number of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1," says the scientist.
RNA Modification and Cancer Connections
Methyladenosine marks on RNA transcripts are a topic that scientists have not been dealing with for very long. They fall into the area of epitranscriptomics — the field of biology that deals with the question of how RNA modifications are involved in the regulation of gene expression. Methyl groups play a key role in this. It is known, for example, that RNA modifications are often misplaced in cancer cells.
NEAT1's Surprising Role in DNA Repair
The experiments conducted by Kaspar Burger and his team show that the frequent occurrence of DNA double-strand breaks causes excessive methylation of NEAT1, which leads to changes in the NEAT1 secondary structure. As a result, highly methylated NEAT1 accumulates at some of these lesions to drive the recognition of broken DNA. In turn, experimentally induced suppression of NEAT1 levels delayed the DNA damage response, resulting in increased amounts of DNA damage.
NEAT1 itself does not repair DNA damage. However, as the Würzburg team discovered, it enables the controlled release and activation of an RNA-binding DNA repair factor. In this way, the cell can recognize and repair DNA damage highly efficiently.
New Avenues for Cancer Therapy
According to the scientists, knowledge about the role of NEAT1 methylation in the recognition and repair of DNA damage could open up new therapeutic options for tumors with high NEAT1 expression. However, it must first be clarified whether these results, which were obtained in simple cell systems, can also be transferred to complex tumor models.
Reference: "NEAT1 promotes genome stability via m6A methylation-dependent regulation of CHD4" by Victoria Mamontova, Barbara Trifault, Anne-Sophie Gribling-Burrer, Patrick Bohn, Lea Boten, Pit Preckwinkel, Peter Gallant, Daniel Solvie, Carsten P. Ade, Dimitrios Papadopoulos, Martin Eilers, Tony Gutschner, Redmond P. Smyth and Kaspar Burger, 1 February 2025, Genes & Development.
DOI: 10.1101/gad.351913.124
Kaspar Burger's research was supported by the German Cancer Aid and the Mildred Scheel Early Career Center for Cancer Research (MSNZ) in Würzburg.
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