METTL1 promotes ribosome biogenesis by regulating CCDC86 through its interaction with NAT10
This study reveals that METTL1 promotes ribosome biogenesis and tumor progression through a novel methyltransferase-independent mechanism by recruiting NAT10 to enhance ac4C modification and stabilize CCDC86 mRNA.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer
Inside every living cell, there is a bustling factory dedicated to building the machines that make proteins. These machines are called ribosomes, and they are essential for life because proteins are the workers that carry out almost every task in the body. To keep up with the demands of growth, especially in rapidly dividing cells like those found in tumors, the cell must constantly churn out new ribosomes. This process, known as ribosome biogenesis, is tightly controlled. When this control breaks down, cells can grow out of control, leading to cancer. For years, scientists have known that a specific enzyme, called METTL1, helps regulate how cells read genetic instructions, but they believed it worked only by adding a tiny chemical tag to a specific type of RNA molecule that helps build proteins. The prevailing view was that METTL1 acted strictly as a chemical editor, and without this editing ability, it would be powerless.
A new study challenges this long-held belief, revealing that METTL1 has a second, surprising job that does not depend on its editing skills at all. Researchers at China Medical University discovered that METTL1 acts as a bridge, physically connecting with another enzyme called NAT10 to stabilize the instructions for making a protein called CCDC86. This protein, in turn, drives the production of ribosomes. The team found that even when they disabled METTL1's ability to add chemical tags, it could still bind to NAT10 and boost the production of ribosomes, proving that its role as a physical connector is just as important as its role as an editor. This discovery uncovers a hidden layer of how cancer cells might hijack their internal machinery to grow, suggesting that blocking this physical connection could be a new way to stop tumors.
The researchers began by looking at data from thousands of human tumor samples to see if METTL1 was more common in cancer than in healthy tissue. They found that METTL1 was indeed present at much higher levels in several types of cancer, including breast, lung, and liver tumors. In these samples, high levels of METTL1 were linked to a poorer outlook for patients. To confirm this, the team examined actual tissue samples from patients with breast and lung cancer. Under a microscope, the cancerous tissue glowed brightly with METTL1, while the healthy tissue next to it showed very little. When they tested this in the lab using cancer cells, they saw that adding more METTL1 made the cells grow faster and form more colonies, while removing it slowed them down. They also found that cells with extra METTL1 were better at forming tumor-like balls in a dish, a sign that they were becoming more aggressive and stem-like.
To understand how METTL1 was driving this growth, the scientists looked at the genetic activity inside the cells. They found that when METTL1 was present, the cells were making more of the raw materials needed to build ribosomes. Specifically, the levels of the RNA strands that form the core of the ribosome were higher. This meant that METTL1 was directly helping the cell build more of these protein-making factories. The team then asked a critical question: how does METTL1 do this? They knew it usually works by adding a chemical modification called m7G to RNA, but they suspected there might be another way. They used a technique to pull METTL1 out of the cell along with any proteins stuck to it, and then identified those partners. One of the strongest partners they found was NAT10, an enzyme known for adding a different chemical tag called ac4C to RNA, which helps protect RNA from breaking down.
The team wanted to know if METTL1 needed its usual editing ability to work with NAT10. They created a version of METTL1 that was broken and could no longer add chemical tags. Surprisingly, this broken version still grabbed onto NAT10 just as tightly as the working version did. This was a major clue that the two proteins were working together in a way that did not require METTL1 to be active. Further experiments showed that METTL1 and NAT10 sit together in the nucleus of the cell, and they physically interact through a specific part of NAT10 called the ac4C catalytic domain. When the researchers removed this specific domain from NAT10, the two proteins could no longer stick together.
The next step was to figure out what this partnership actually did to the cell's genetic instructions. The researchers identified a specific gene called CCDC86 that seemed to be the target of this METTL1-NAT10 team. They found that when METTL1 was present, it helped recruit NAT10 to the RNA instructions for CCDC86. Once NAT10 was there, it added the protective ac4C tag to the RNA, which made the instructions last longer and allowed the cell to make more of the CCDC86 protein. Crucially, even the broken, non-editing version of METTL1 could still recruit NAT10 to do this job. However, if the researchers blocked NAT10 or removed its ability to add the ac4C tag, the boost in CCDC86 disappeared. This proved that METTL1 was acting as a recruiter, bringing NAT10 to the right place to stabilize the CCDC86 message.
Finally, the team tested whether CCDC86 was the reason the cells were growing so fast. When they reduced the amount of CCDC86 in the cells, the cells stopped growing as quickly and lost their ability to form tumor spheres. They also found that without CCDC86, the cells could not build ribosomes as efficiently, and the overall production of proteins slowed down. This confirmed that CCDC86 is a key driver of ribosome production and tumor growth. The study concludes that METTL1 promotes cancer growth not just by editing RNA, but by acting as a scaffold that brings NAT10 to the CCDC86 RNA, protecting it and ensuring the cell has enough ribosomes to fuel its rapid expansion. This finding suggests that the physical interaction between these proteins is a vital mechanism in cancer, one that operates independently of the chemical editing METTL1 is famous for.
Drowning in papers in your field?
Get daily digests of the most novel papers matching your research keywords — with technical summaries, in your language.