Unveiling the Power of Nuclear Speckles: Central Players in Gene Expression Control

Researchers at the University of California, Irvine, have revealed that nuclear speckles, a membraneless structure within the nucleus, function as pivotal centers for pre-mRNA 3′ end processing. This finding enhances our comprehension of how the spatial organization within cells affects gene expression, potentially paving the way for new treatments for disorders associated with RNA processing irregularities.

Featured in Molecular Cell, the research indicates that RBBP6, a vital component in pre-mRNA 3′ end processing, is localized to nuclear speckles through its intrinsically disordered region.

This localization is crucial for effective pre-mRNA 3′ end processing in human cells, with over 50% of genes undergoing 3′ end processing at nuclear speckles, as discovered by the researchers. These observations emphasize the integrative function of nuclear speckles in harmonizing transcription, splicing, and 3′ end formation.

“Pre-mRNA 3′ end processing constitutes a vital stage in mRNA biogenesis, with its misregulation linked to various ailments, including cancer,” said corresponding author Yongsheng Shi, Ph.D., a professor of microbiology and molecular genetics at UC Irvine. “Our research, for the first time, pinpoints where pre-mRNA 3′ end processing takes place in the cell. By comprehending this spatial arrangement, we can more effectively interpret how disturbances in these processes lead to illness.”

For several years, the scientific community has speculated on the role of nuclear speckles within cells, especially regarding other mRNA processing phases, such as splicing. However, directly examining these functions has proven difficult due to the intricate nature of RNA processing machinery.

This new study, spearheaded by first author Yoseop Yoon, Ph.D., addressed this challenge by confirming that RBBP6 localizes to nuclear speckles and differentiating its functional domain from the one responsible for localization. Through this differentiation and utilizing advanced imaging, sequencing, and biochemical methods, the researchers could directly assess whether the localization of RBBP6 to nuclear speckles is essential for pre-mRNA 3′ end processing.

“In addition to its critical role in mRNA processing within nuclear speckles, RBBP6 also associates with numerous well-known tumor suppressor proteins, such as p53, through its long intrinsically disordered region,” explained Shi. “These proteins are recognized for recruiting their target genes to nuclear speckles to boost gene expression, but the mechanisms behind this remain elusive. Our future investigations will delve into these interactions and their consequences for gene regulation and cancer.”