Researchers create first map of cancer's Achilles heel, the spliceosome | Science

This is a surprising and counterintuitive fact. The 30 billion cells that make up a person are Same instruction manualWhether it's the neurons in your brain or the bone in your big toe. This common manual acts like a rare cookbook, allowing each cell to prepare different dishes from the same recipe. Imagine the classic paella ingredients listed on the page: rice, chicken, rabbit, saffron, garlic, oil, etc. Each cell reads only a few selected words, with one cell making paella and another making garlic fried rabbit or rice with chicken. Feet are not similar to brains because the same DNA yields different results. On Thursday, a team of scientists from Barcelona's Genome Regulation Center achieved a historic milestone by creating the first map of the spliceosome, the complex machinery responsible for this process.

geneticist Juan Valcarcel62 points out that the process is actually a bit more complicated. “Words are written into our DNA, so they are separated by bunches of meaningless letters. Cells are separated from what they have in order to remove the meaningless parts in a process called splicing. We have developed what we think is the most complex machine,” explains Valcarcel.

Following the same example, the DNA recipe would be written as follows: rice osdlsdkjg chicken ugdlsgjls rabbit igosgsjodi saffron bpnemrac garlic effeu oil. The spliceosome machinery, which is made up of 150 proteins, separates things that don't make sense, such as rice, chicken, rabbit, saffron, garlic, and oil. And the second phenomenon, known as alternative splicing, selects only certain words, such as rice and chicken or rabbit and garlic.

Human DNA is a two-meter-long molecule that is folded inside each cell. can be roughly divided into 20,000 sections, called genes It contains recipes for producing proteins essential to life, such as collagen for bones, hemoglobin for oxygen transport in the blood, and myosin for muscles. Thanks to the action of spliceosomes, human cells have only 20,000 genes but can produce 100,000 different proteins.

Valcarcel has been studying this complex mechanism since 1986. Errors in reading spliceosomes can cause millions of errors. in case of canceras well as rare neurodegenerative diseases. Valcarcel's team spent more than a decade creating the first map of the spliceosome. Published in a magazine on Thursday scienceintroducing the world's best research. This machine consists of 150 proteins and an additional 150 proteins that act as regulators on the outside. The researchers carefully inactivated 300 proteins one by one to observe their effects. For their experiments, the authors used cells from Henrietta Lacks, a tobacco worker who died in Maryland of uterine cancer in 1951.

“There's a lot of potential,” Valcarcel said. “What's really interesting is the alternating connections. The same gene can produce proteins that kill cells, proteins that inhibit cell death, or proteins that cause cancer cells to grow in large numbers or not at all. “If we understand these mechanisms, we can reverse these decisions or use genetic engineering to create customized proteins,” says the geneticist. “This new study provides a kind of functional map of the 300 components of the spliceosome, which tells us what they are doing inside cancer cells when they read messages from genes. I will give it to you.”

Valcarcel is sitting in a large conference room in the Genome Control Center building. Next to him is a Polish biologist. Malgorzata Rogalska37 years old, lead author of the study. “Understanding function and understanding structure are completely different. Structure is a perfect and stable image, but perfect conditions do not exist in our bodies. By understanding how to adapt, we were able to create the first map,” says Rogalska.

Biologists liken splicing to a movie editing process in which dozens of participants can take control and change the meaning of a scene. One of her main conclusions is that the 300 components of the spliceosome are interconnected, and failure of one of them can cause a domino effect. The researchers manipulated the SF3B1 component, mutations of which have been linked to a variety of cancer types, including breast cancer, melanoma, and leukemia. In their experiments, this change caused a series of errors, Cancer cell proliferation.

“This is a potential Achilles' heel that can be exploited to design new treatments. Our map provides a way to discover these weaknesses,” says Valcarcel. Her spliceosome map is now available to the scientific community.

scientist Marina SernaShe studied the structure of spliceosomes at the National Cancer Research Center in Madrid, and although she was not involved in the research, she praised the work of her colleagues in Barcelona. “Splicing has fundamental implications in cancer,” she says. “This study not only identifies all the regulatory factors that, when altered, clearly affect spliceosome function, but also reveals how these factors control themselves and each other in very complex ways. We also found that adjusting one element does not affect only one other element, but directly affects almost every other element.”

Serna emphasizes the magnitude of the challenge. A water molecule consists of two hydrogen atoms bonded to one oxygen atom (H₂O), while hemoglobin, the protein that gives blood its red color, has the formula C₂₉₅₂H₄₆₆₄N₈₁₂O₈₃₂S₈Fe₄. The structure of a single protein is already complex, but its 300-component spliceosome is even more formidable. “And the same protein exhibits different conformations and interactions at different stages of the splicing cycle. The spliceosome is one of the most complex molecular machines known,” the researchers say.

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