The nucleolus is a distinct and dynamic structure found within the nucleus of eukaryotic cells. It lacks a surrounding membrane, setting it apart from other organelles, and typically forms around specific chromosomal regions known as nucleolar organizing regions (NORs). Composed of ribosomal RNA (rRNA) genes, newly synthesized rRNA, and various proteins, the nucleolus is a highly organized and active cellular component. Its size and appearance can fluctuate significantly depending on the cell’s metabolic activity, reflecting its responsiveness to cellular demands.
The Ribosome Factory
The primary function of the nucleolus is the production of ribosomes, a process termed ribosome biogenesis. Ribosomes are the cellular machinery responsible for protein synthesis, a process essential for all living cells. Actively growing cells require a substantial number of ribosomes, synthesizing hundreds per second to meet their protein production needs.
The process begins with the transcription of ribosomal RNA (rRNA). The genes for 5.8S, 18S, and 28S rRNAs are located within the nucleolus and are transcribed by RNA polymerase I, forming a large precursor RNA molecule known as 45S pre-rRNA in mammals. This 45S pre-rRNA then undergoes a series of modifications and is cleaved by specific enzymes to yield the mature 18S, 5.8S, and 28S rRNAs. A fourth rRNA, the 5S rRNA, is transcribed by RNA polymerase III outside the nucleolus but is subsequently transported into the nucleolus for the next stage of ribosome assembly.
Following rRNA synthesis and processing, ribosomal proteins, which are produced in the cytoplasm, are imported into the nucleolus. Inside the nucleolus, these imported proteins associate with the newly processed rRNAs to form precursor ribosomal particles. These particles mature into two distinct components: the small (40S) and large (60S) ribosomal subunits. Once fully assembled, these subunits are exported from the nucleus into the cytoplasm, where they combine to form functional 80S ribosomes, ready to undertake protein synthesis.
Beyond Ribosomes: Other Cellular Roles
While ribosome biogenesis is its most recognized role, the nucleolus participates in a range of other cellular processes. The nucleolus acts as a central hub where various cellular signals converge.
One such role involves the regulation of the cell cycle. The nucleolus functions as a sensor for growth-related signals, influencing the progression of cell division. If the synthesis or processing of rRNA is disrupted, the nucleolus can trigger a halt in cell cycle progression, serving as a quality control mechanism. During cell division, the nucleoli temporarily disassemble and then reform in the daughter cells, demonstrating their dynamic nature and close ties to cellular proliferation.
The nucleolus also plays a part in the cell’s stress response. It acts as a signaling hub, detecting various cellular stresses such as nutrient deprivation, DNA damage, oxidative stress, and heat shock. When ribosome biogenesis is disrupted, a condition known as nucleolar stress, the nucleolus activates specific pathways that can lead to cell cycle arrest or programmed cell death, helping the cell cope with adverse conditions.
Beyond rRNAs, the nucleolus is involved in the processing of other types of RNA, including small nucleolar RNAs (snoRNAs). These snoRNAs are important in guiding the modification and processing of rRNAs, contributing to the precision of ribosome assembly. Additionally, the nucleolus interacts with various viruses. Many viruses manipulate the nucleolus during their replication cycles.
When Things Go Wrong: Nucleolus and Disease
Dysfunction of the nucleolus can have significant consequences for human health, contributing to a range of conditions often referred to as “nucleolopathies.”
Abnormalities in the nucleolus are frequently observed in cancer cells. Cancer cells typically exhibit a high demand for ribosomes to support their rapid proliferation, which often leads to increased nucleolar activity and, consequently, larger nucleoli. Disruptions in the nucleolar stress pathways can contribute to the development and progression of cancer. Some anti-cancer drugs are designed to target nucleolar activities, while others may cause nucleolar stress as an unintended side effect, impacting both cancerous and healthy cells.
Nucleolar dysfunction and nucleolar stress have also been implicated in neurodegenerative disorders. Conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) have been linked to impaired nucleolar activity. Research suggests that proper nucleolar function is necessary for the survival of neurons.
Furthermore, defects in the components of ribosomes or the genes involved in ribosome biogenesis can lead to a group of genetic disorders known as ribosomopathies. Examples of these conditions include Diamond-Blackfan anemia and Treacher Collins syndrome. A notable aspect of many ribosomopathies is an increased susceptibility to cancer, underscoring the interconnectedness of ribosome production and disease.