Delicate balancing act determines how many genome gateways form in cells

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The nuclei in our cells are miniature warehouses safeguarding the genetic blueprint for the body’s biologic machinery.

As warehouses go, nuclei are more like libraries than bank vaults. Too many cellular components need access to the genome to lock it down like Fort Knox. Instead, large groupings of more than 1,000 individual protein molecules called nuclear pore complexes (NPCs) pepper the dividing membrane, serving as gateways for materials and messages entering and exiting the nucleus.

While the basic need for this shuttle service is constant, scientists have shown that cells dynamically adjust their amounts of NPCs like a retail store opening more or fewer checkout lines throughout the day. These fluctuations in genome access points have been observed in different cell types, stages of development, environmental conditions and in diseases such as neurodegeneration and cancer.

“As important as NPCs are for sustaining healthy cells, and despite the connections we and others have found to disease, we still have a lot to learn about how cells control the production of these genome gateways,” said Maximiliano D’Angelo, PhD, associate professor in the Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.

D'Angelo and his research team at Sanford Burnham Prebys published findings March 31, 2025, in Cell Reports revealing the results of screening the entire human genome to find factors influencing how many NPCs are assembled.

“Our goal was to identify the modulators of pore formation,” said Stephen Sakuma, PhD, postdoctoral researcher at the Salk Institute, former graduate student in the D’Angelo lab and lead author of the study. “By discovering the mechanisms cells use to modulate pore formation, we may find new therapeutic approaches."

The research team found that the most influential players in the process were parts of opposing teams: the production crew making new proteins and the janitorial staff that recycle proteins and dispose of excess or misshapen proteins.

“It caught our eye that top regulators were pieces of the protein translation or degradation machinery,” said D’Angelo, senior and corresponding author of the study. “While it may seem intuitive because these processes would affect the number of nucleoporin proteins used to construct pores, this had not previously been investigated.”

The scientists also uncovered the role of cellular actors involved in maintaining the messenger RNA (mRNA) that carries codes for building proteins out of the nucleus. The investigators detailed the involvement of a grouping of proteins called the CCR4-NOT complex, which is responsible for triggering the disposal of mRNA.

“We found that this complex reduces the mRNA levels, which diminishes the translation of NPC building blocks,” said Sakuma. “This means it is possible to regulate the number of NPCs in different ways by altering protein translation or degradation, or by stabilizing or destabilizing mRNAs.”

In addition to learning more about these top regulators, the researchers also are studying other factors identified in the genome-wide screen that may be employed to fine-tune levels of NPCs, as well as searching for small molecules that can manipulate NPCs.

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

“Our previous work discovered that reducing the number of NPCs is a promising strategy for cancer treatments and we are now developing methods to do that,” said D’Angelo. The group is also working to increase NPC function in brain cells afflicted with neurodegenerative diseases such as dementia.

Additional authors include: 

Marcela Raices, Dana Mamriev, Charles I. Fisher and Susanne Heynen-Genel, from Sanford Burnham Prebys Ethan Y.S. Zhu, from the New York University Grossman School of Medicine The study was supported by the National Institutes of Health, the National Cancer Institute and the American Cancer Society.

The study’s DOI is 10.1016/j.celrep.2025.115468.

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