24 May 2012

RNA is the protector of the genome

Scientists at the Institute of Molecular Oncology (Milan, Italy) and the Riken Research Center, Yokohama, Japan, working under the leadership of Fabrizio D'adda di Fagagna, identified a new unexpected function of RNA. It turned out that its previously unknown class – DDRNA (DNA Damage Response RNA, RNA reacting to DNA damage) – plays a key role in the activation of molecular signaling mechanisms that protect the genome from damage as a result of external and internal factors.

Given the importance of cells responding to DNA damage in old age, when malignant tumors appear in the body, as well as in the treatment of cancer, this discovery may open up new promising prospects for doctors.

For decades, experts have believed that RNAs are a kind of "subordinate" DNA – functional links in the process of translation from the language of nucleotides to the language of amino acids. However, in recent years, this simplified scenario has become much more complicated due to the discovery of new classes of DNA involved in the work of various intracellular mechanisms.

The discovery of the authors added another plot to this scenario. It turned out that every time DNA damage occurs on a damaged sequence, non-coding RNAs of a previously unknown class are synthesized. The purpose of the appearance of these molecules is to trigger molecular signaling mechanisms that give the cell an alarm signal and activate DNA repair systems.

The uniqueness of this mechanism lies in the fact that, despite significant differences in structure, sequence and modes of action, the work of all previously described RNA subtypes is subordinated to a common goal: they all (at different levels) provide regulation and functional organization of gene expression – synthesis (or its termination as a result of RNA interference) of the corresponding proteins. In contrast, the new subtype of RNA is a defender of the integrity and stability of genes.

RNA reacting to DNA damage was discovered during experiments on cell lines, in which researchers created stressful conditions that could lead to DNA damage in cell nuclei. After that, they sequenced the sequences of all the RNAs expressed in the damaged cells.

The results of the analysis clearly indicated that DNA damage triggers the transcription of short RNA molecules on the damaged sequence. Further studies have revealed the key role belonging to this class of RNA in triggering the mechanisms of DNA damage repair.

For many years, di Fagagna and his group have been studying the mechanisms underlying malignant transformation and physiological aging of cells, as well as the relationship between these phenomena and the violation of the integrity of the genome. In fact, these closely related phenomena are different sides of the same coin. The fact is that DNA damage leads to a temporary loss of the cell's ability to divide. This avoids rearrangements of chromosomes and mutations fraught with the formation of malignant tumors. If it is impossible to repair DNA damage, the cell usually stops dividing completely and enters the phase of physiological aging. However, in some cases, the protective mechanisms do not work and the cell begins to proliferate uncontrollably, giving rise to a cancerous tumor.

The discovery of a new class of RNA complements the molecular picture of events occurring in the cell during DNA damage, and opens up new possibilities for interpreting the aging processes, as well as the mechanisms of tumor transformation and tumor progression. In particular, the authors plan to find out whether the mechanisms of synthesis of RNA reacting to DNA damage in tumor cells have been changed and how these changes can affect the process of tumor origin and development.

Article by Sofia Francia et al. Site-specific DICER and DROSHA RNA products control the DNA-damage response is published in the journal Nature.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of ScienceDaily:
RNA: From Messenger to Guardian of Genome Integrity.


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