Macromolecules’ stability governs and affects most cellular processes, well-being, and the life cycle. Beyond the cellular level, it plays a key role in development, physiological responses, and homeostasis. The two sister nucleic acids, RNA and DNA, share many similarities, but they differ greatly in their respective half-lives. DNA is an extremely stable molecule that can persist for the entire life of the organism. However, RNA is relatively unstable and degrades within seconds to ten minutes. Given their crucial role in various processes, particularly in the regulation of gene expression, their stability shapes the landscape of cellular dynamics. Recently, a team at the German Center for Neurodegenerative Diseases (DZNE) in Dresden showed that certain nuclear RNAs can indeed persist for years. In this article, we will discuss RNA stability, turnover, and these newly discovered nuclear RNAs that can survive for as long as two years.
The Dynamic Nature of RNA Stability:
RNA stability refers to the ability of an RNA molecule to resist degradation and persist within the cellular environment. Different families of RNAs have different lifespans:
Messenger RNA (mRNA): Among the most dynamically regulated RNA species, mRNA molecules act as bridges that link the genetic information stored within the DNA to the translation machinery that synthesizes fully functional proteins. The stability of mRNA is highly dynamic to meet the demands of gene expression. It is finely tuned with various mechanisms such as transcriptional regulation, RNA processing, and RNA decay pathways exerting control over its lifespan.
Ribosomal RNA (rRNA) and Transfer RNA (tRNA): Unlike mRNA, which is transient, rRNA and tRNA are remarkably stable. They play crucial roles in the ribosome and aid in protein synthesis. These structural RNAs are abundant and robust, with rRNA lasting for days to weeks in the cell. Their stability is crucial for preserving the integrity and functionality of the protein synthesis mechanism, guaranteeing accurate and efficient translation processes.
Regulatory RNAs: These RNAs, such as miRNAs, affect the stability of other RNAs like mRNAs. These small non-coding RNAs orchestrate diverse cellular processes ranging from development to immune response. The stability of regulatory RNAs is tightly controlled, with mechanisms such as RNA interference pathways and RNA-binding proteins governing their turnover rates and activity profiles.
Factors Influencing RNA Stability:
Several factors contribute to the stability of RNA molecules, dictating their lifespan and functional impact within the cell:
Sequence features: The nucleotide sequence can affect stability both positively and negatively. Some unstable motifs can be prone to degradation and may be targeted to RNA decay pathways. In contrast, some secondary and tertiary structures can increase the stability of the molecule.
RNA binding proteins: The protein interactome of an RNA molecule can also determine its lifespan. Some proteins can promote degradation of the RNA, while others can protect the nucleic acid from degradation. This depends on their binding specificity and regulatory function.
RNA modifications: Post-transcriptional modifications such as methylation and pseudouridylation can affect RNA stability in various ways. They modulate the interaction of RNA molecules with RNA-binding proteins and RNA decay machinery. They also help RNAs fold into their functional tertiary structure, which can drastically affect stability.
Can RNAs Persist for a Long Period of Time?
In a recent study, certain nuclear RNAs were shown to be “stably retained” in neuronal cells of mice. Using in vivo pulse-chase labeling of transcripts with a modified uridine analog, 5-ethynyl uridine (EU), researchers traced de novo-synthesized RNA molecules throughout brain development and found specific types of nuclear RNAs, named long-lived RNAs (LL-RNAs), that persisted for as long as 2 years. These RNAs were localized in the nucleus of several neuronal cells, such as the dentate gyrus and radial glia–like adult neural stem cells. These LL-RNAs were identified as protein-coding RNAs and noncoding RNAs. Satellite RNAs (satRNAs) were enriched within the LL-RNAs population. SatRNAs are known to be associated with constitutive heterochromatin, indicating that these LL-RNAs play an important role in maintaining heterochromatin integrity.
In conclusion, while RNA molecules generally have a short lifespan, some RNA molecules that play a role in heterochromatin organization can persist for a long period of time. RNA biology is a hot research spot, and every day we gain more insights into this master regulator of gene expression.
References:
1. Baudrimont, A. et al. Multiplexed gene control reveals rapid mRNA turnover. Science Advances 3, e1700006 (2017).
2. Zocher, S. et al. Lifelong persistence of nuclear RNAs in the mouse brain. Science 384, 53–59 (2024).
RNA Stuff 