A recent study published on July 29, 2025, sheds light on the intricate relationship between pre-rRNA processing and the architecture of the nucleolus, a critical hub for ribosome production in eukaryotic cells. The findings shed light on the associations between nucleolar dysfunction and human disorders such as cancer, neurodegeneration and developmental disorders. This new pioneering work shifts paradigms in our understanding about ribosome biogenesis. It further opens the door to a new, paradigm-shifting model of nucleolar organization.
Academics turned their attention to the nucleolus, a sub-cellular structure known mostly for its involvement in ribosome biogenesis. Historically, we knew the concept of rRNA synthesis and processing occurring inside morphologically well-defined structural units, termed as fibrillar centers (FC) and dense fibrillar components (DFC). At the same time, ribosome assembly occurs in granule compartments (GC). The latest study shows that this process is less straightforward than we’ve long believed.
Nucleolar Dysfunction and Disease
In addition to cancer, nucleolar dysfunction has been associated with several other diseases such as neurodegenerative disorders. Although it seems to be minor, the nucleolus has a crucial part in producing ribosomes, which are critical for translating proteins. Any disruption in this elaborate dance can set off a chain reaction affecting overall cellular function and lead to the onset of disease.
As described in their study, appreciating the nucleolar architecture is key to appreciating its roles in health and disease. Its disruption can result in aberrant cellular proliferation and mitosis, which are hallmarks of cancer. Indeed, neurodegenerative diseases frequently show evidence of disrupted nucleolar activity. Investigators across the world are beginning to crack the codes of nucleolar organization. They’re figuring out how it’s coordinated with pre-rRNA processing to uncover new potential therapeutic targets.
Insights into Ribosome Biogenesis
From the genetics, it is clear that nucleolar sub-structures are upheld by 5′ external transcribed space (5′ ETS)-centered small subunit (SSU) processing. Oligos complementary to the 5′ ETS region of SSU pre-rRNA were used as antisense oligonucleotides to arrest pre-rRNA processing. Interestingly, this inhibition recapitulated the structural defects often seen in slowly proliferating cells.
Together, our results reveal that spatiotemporal coordination between pre-rRNA processing and nucleolar architecture is critical for robust ribosome production. Our model suggests that the spatial organization of nucleolar processing events into sub structures enhances the functional outcome of nucleolar structures. This further coordination is especially important in the context that ribosome production needs to be carefully tuned to the needs of the cell.
Comparative Analysis of Nucleoli
Our study aims to understand the differences between these bipartite nucleoli present in anamniotes, such as zebrafish. It reviews the multilayered nucleoli seen in amniotes. Unlike their counterparts, bipartite nucleoli do not have a clear FC-DFC interface and show different 5′ ETS distributions and slower pre-rRNA diffusion rates. Taken together, these differences indicate that the structural organization of nucleoli may serve to impact the effectiveness of ribosome biogenesis between species.
Our understanding of how evolution has sculpted different nucleolar architectures, researchers systematically compare diverse nucleolar architectures. Their results shed light on the remarkable evolutionary strategies different organisms use to maximize ribosome production. These exciting findings highlight how a deeper appreciation of these differences can point to new avenues in understanding ribosome-associated diseases.
