Molecules accumulated at the chromosome tips are known to play a key role in preventing DNA damage. Research led by a team at the École Polytechnique Fédérale de Lausanne (EPFL), in Switzerland, has now developed new insights into how these molecules lead to specific chromosome sections. Their findings, reported on Nature, “TERRA lncRNA̵7;s RAD51-dependent recruitment of telomeres through R-loops,” could help scientists better understand the processes that control cell survival in aging and cancer.
DNA strands called telomeres form protective caps at the ends of the chromosome, acting on the aglet of a shoe sole that prevents the lace from frying. “Telomeres — recurrent, non-coding nucleotide motifs and related proteins found at the ends of the eukaryotic chromosome — mediate genome stability and determine cellular lifespan,” explains the first author Marianna Feretzaki, PhD, at EPFL, and colleagues. But as the cells split, the telomeres gradually became shorter, making the protective cover less effective. When telomeres eventually become too short, the cell stops dividing. Telomere shortening and malfunction are associated with cell aging and age-related diseases, including cancer.
Scientists know that RNA species called TERRA (telomeric-containing RNA) help to control the length and function of telomeres. In 2007 postdoc Claus Azzalin, PhD, of EPFL professor Joachim Lingner, PhD, discovered that TERRA belongs to a class of molecules called long noncoding RNAs. These are RNA molecules that are not translated into proteins, but instead act as structural elements of the chromosome. TERRA accumulates at the ends of the chromosome, signaling that telomeres must be elongated or fixed. “Telomeric receptor-containing RNAs (TERRA) are a class of long-term noncoding RNAs (lncRNAs) transmitted from the ends of the chromosome,” the authors further explain. “… these RNAs regulate telomeric chromatin structure and telomere retention by telomere-extending enzyme telomerase and homology directed at homology.”
However, it is not clear how TERRA directs the chromosome tips and stays there. “The mechanisms by which TERRA is recruited at the ends of the chromosome remain poorly interpreted,” investigators said. As Lingner puts it, “The telomere makes up only a tiny bit of total chromosomal DNA, so the question is‘ how does RNA find its home? ’” To address this question, postdoc Marianna Feretzaki and others in the Lingner teams at EPFL and Lumir Krejci, PhD, at Masaryk University in the Czech Republic, set out to study the mechanism by which TERRA accumulates in telomeres, as well as the proteins involved in this process.
By visualizing TERRA molecules under a microscope, the researchers found that a short stretch of RNA was essential to bring it to telomeres. Their experiments showed that when TERRA reached the end of chromosomes, many proteins control its association with telomeres. Among these proteins, RAD51 plays a particularly important role, Lingner said.
RAD51 is a well-known enzyme involved in the repair of broken DNA molecules. It seems that the TERRA protein also helps to stay in the telomeric DNA, to form an ‘RNA-DNA hybrid’ Molecule. Scientists thought this type of reaction, leading to the formation of a three-stranded nucleic acid structure, mainly occurred during DNA repair. Newly reported results suggest that it may also occur in chromosomes that terminate when TERRA binds to telomeres. “It’s paradigm-shifting,” Lingner commented.
The researchers also found that short telomeres recruited TERRA better than long telomeres. “Cells carrying short telomeres recruited TERRA better than cells with long telomeres, as seen in the short-term or stable expression of TERRA,” they commented. And while the mechanism behind this phenomenon is unclear, the researchers thought that when telomeres became too short, either because of damage or because the cell was split too many times, they recruited TERRAs. molecules. DNA… maikling short telomeres should be more accessible in TERRA recruitment or maintenance; Alternatively, long telomeres may contain active systems that emit TERRA, “they wrote. This recruitment mediates with RAD51, which also promotes the elongation and repair of telomeres.” TERRA and RAD51 help to prevent accidental loss or shortening of telomeres, “Lingner added.” That is an important function. “
The authors stated that the observed base formation between TERRA and telomeric DNA provides a mechanism for directing TERRA to its primary area of action at the chromosome tips. “Our data show the mechanism by which TERRA is recruited to the end chromosome by invading the RNA strand,” they noted. “… TERRA recruitment seems to have taken place through a process that strongly resembles strand-invasion and homology-search mechanisms exploited by all living organisms during HDR DNA repair, and where is also characteristic of telomere consolidation of the ‘alternative elongation of telomeres Mechanism’ (ALT) in cancer cells. “
Given the role of telomeres in health and disease, it will be important to see how the newly discovered mechanism, which has been deducted from observations of living cells and reproduced in test tubes, is controlled in very difficult cellular environment, Lingner said. “We put in place a model, which is supported by the data we have – but often in science, it turns out that the model needs to change. There may be more surprises.”
Next, the team plans to address other key questions, including whether RAD51 interacts with other noncoding RNAs with chromosomes. Researchers also aim to better identify the machinery that interacts with TERRA’s interaction with chromosomes, and perform the functions enabled by this association. “There are many questions that remain open,” Lingner acknowledged.