Ribonucleic acid (RNA) is a fundamental molecule in all living organisms, playing diverse roles in genetic information expression. While DNA holds the master blueprint, RNA molecules act as intermediaries, translating this blueprint into proteins and other cellular components. Among RNA types, small interfering RNA (siRNA) is a powerful, naturally occurring molecule that controls genetic information, influencing gene expression.
What is Small Interfering RNA
Small interfering RNA (siRNA) is a class of double-stranded, non-coding RNA molecules, typically 20 to 25 base pairs long. These short molecules have a specific structure with characteristic ends. Unlike messenger RNA (mRNA), which carries genetic instructions to make proteins, siRNA does not directly encode proteins. Instead, its primary function is to participate in RNA interference (RNAi), where it can silence specific genes.
The production of natural siRNAs within a cell is often catalyzed by Dicer, an enzyme that cleaves longer double-stranded RNA (dsRNA) molecules into these shorter fragments. These longer dsRNAs can originate from various sources, including viral infections, hairpin structures, or complementary RNA molecules. The structure of siRNA allows it to be recognized and utilized by cellular machinery.
How Small Interfering RNA Silences Genes
The process by which small interfering RNA silences genes is known as RNA interference (RNAi), targeting specific messenger RNA (mRNA) molecules for degradation. This prevents mRNA from being translated into proteins. Dicer processes longer double-stranded RNA precursors into 20-25 base pair siRNA duplexes with short overhangs.
Once formed, the siRNA duplex is incorporated into the RNA-induced silencing complex (RISC). Within RISC, one siRNA strand (the “guide strand”) is retained, while the other is discarded. The guide strand, now part of the active RISC, scans for and binds to target mRNA molecules with complementary sequences.
Upon binding to its complementary mRNA target, the RISC, guided by the siRNA, activates its enzymatic activity through an Argonaute protein. This enzyme then cleaves the target mRNA molecule at a specific location where the siRNA guide strand binds. The fragmented mRNA is rapidly degraded by other cellular enzymes. This degradation of mRNA achieves gene silencing, preventing protein production.
Small Interfering RNA in Biology
Small interfering RNA plays a multifaceted role in the natural biological processes of living organisms. One of its primary functions involves cellular defense against foreign genetic invaders, such as viruses. When viruses infect a cell, they often produce double-stranded RNA, which the cell’s Dicer enzyme recognizes and processes into siRNAs. These siRNAs then guide the RISC complex to degrade the viral mRNA, thereby inhibiting viral replication and preventing the infection from spreading.
Small interfering RNA also contributes to maintaining genomic stability by silencing transposable elements, often referred to as “jumping genes”. These genetic elements can move around the genome, potentially causing mutations and disrupting gene function. By targeting and silencing the RNA transcripts produced by these transposons, siRNA helps to keep them in check, safeguarding the integrity of the organism’s genetic material. Beyond defense, siRNAs are involved in regulating gene expression, influencing various cellular processes by fine-tuning the levels of specific proteins. This regulatory capacity allows cells to adapt to changing environments and maintain proper cellular function.
Small Interfering RNA in Medicine
The precise gene-silencing ability of small interfering RNA has opened up applications as a therapeutic tool in medicine. Scientists can design synthetic siRNAs to specifically target and silence genes involved in causing various diseases. This approach addresses diseases at their genetic root by preventing harmful protein production or inhibiting processes that contribute to illness.
One prominent area of research and development for siRNA-based therapies is in treating genetic disorders. For instance, Patisiran (Onpattro) is an approved siRNA therapeutic that targets the transthyretin gene, reducing the production of both normal and mutated transthyretin protein in patients with hereditary transthyretin-mediated amyloidosis. Another example is Givosiran (Givlaari), approved for acute hepatic porphyria, which works by modulating ALAS-1 mRNA levels. These therapies demonstrate the ability of siRNAs to address underlying genetic defects.
Small interfering RNA therapies are also being explored for viral infections. By designing siRNAs that target specific viral RNA sequences, it is possible to stop viral replication and spread. Research is ongoing for conditions such as HIV and hepatitis C, where siRNAs could offer a new treatment strategy by degrading viral genomes and adapting to mutations. In cancer treatment, siRNAs are being investigated to silence oncogenes, which are genes that promote cancer growth, or to inhibit genes that contribute to tumor survival and metastasis.
Despite their promise, delivering siRNAs to target cells within the body remains a challenge, as these molecules are easily degraded and can trigger immune responses. Researchers are developing various delivery methods, including lipid nanoparticles, polymer-based nanoparticles, and viral vectors, to protect siRNAs and ensure their efficient uptake by cells or tissues. These advancements are steadily bringing siRNA-based therapies closer to widespread clinical use, offering new treatment possibilities for a wide range of diseases.