The delicate act of balance determines how many genomes are formed in cells

As warehouses go, the nuclei resemble libraries more than bank vaults. Too many cell components need access to a genome to lock it as Fort Knox. Instead, large groups of more than 1,000 individual protein molecules called nuclear pores complexes (NPC) peppers with division for division, and serve as applicants for materials and messages that enter and come out of the core.

Although the basic need for this service is constant, scientists have shown that the cells dynamically adjust their amounts of NPC, such as a retail store that opens more or less logs for a checkout during the day. These fluctuations in the accessories of the genome have been observed in different cell types, developmental stages, environmental conditions and diseases such as neurodegeneration and cancer.

“As important as NPCs are for maintaining healthy cells, and despite the relationships we considered the disease, we still have a lot to know about how cells control the production of these genomes,” said Maxilianiano D’Angelo, a doctor of science, an associate professor at Cancer Metabolism and Microcolate Program in Sanford Burnham PREBS.

D’Angelo and his research team in Sanford Burnham Prebis published findings on March 31, 2025. Cell Reports Discovering the results of a whole human genome to find factors that affect how much NPC is composed.

“Our goal was to identify the modulators of the formation of pore,” said Stephen Sakuma, a doctor of science, a postdoctoral researcher from the Salk Institute, a former graduate student at D’Angelo Laboratory and the leading author of the study. “By discovering the mechanisms used by cells to modulate pore creation, we can find new therapeutic approaches.”

The research team revealed that the most influential players in the process were parts of the opposing teams: a production crew that made new proteins and lamb staff recycling proteins and deviates excess or failure of protein.

“It has noticed that top regulators are pieces of translation machinery or protein breakdown,” said D’Angelo, the older and correspondent author of the study. “Although it may seem intuitive because these processes would affect the number of nucleoporin proteins used for pore construction, this has not been tested before.”

Scientists have also discovered the role of cell actors involved in the maintenance of RNA messengers (MRNA) that carries codes to build protein from the nucleus. Investigators have described in detail the involvement of protein grouping called the CCR4-NOT complex, which is responsible for starting the MRNA deflection.

“We have found that this complex reduces the level of MRNA, which reduces the translation of NPC building blocks,” Sakuma said. “This means that it is possible to regulate the number of NPC in different ways by changing translation or degradation of protein or stabilization or destabilization of mrna.”

In addition to learning more about these top regulators, researchers also study other factors identified on the screen across the genome that can be used on fine NPC levels, as well as in the search for small molecules that can manipulate NPC.

With additional research, D’Angelo and his team aim to find ways to reduce NPC in reckless growing cancer cells to stop or delay the progression of the disease.

“Our previous work has revealed that the reduction of NPC is a promising strategy for cancer treatment and now we are developing methods for that,” said D’Angelo. The group also works to increase the NPC function in brain cells affected by neurodegenerative diseases such as dementia.

Additional authors include:

• Marcela Raices, Dana Mamriev, Charles I. Fisher and Susanne Heynen-Genel, of Sanford Burnham Pregis
• Ethan Ys Zhu, from Faculty of Medicine, University of New York

The study was supported by the National Institutes of Health, the National Institute of Cancer and the American Cancer Society.