Cellular function and degradation mechanisms of TRIM52

Through evolution, humans and other higher primates have gained means to support their increasingly complex bodies. An important aspect of this is to protect their genetic material from damage during cell duplication. Full elucidation of the human genetic code, has allowed scientists to identify factors that have been developing rapidly in human evolution, and as such may have important functions in regulating human-specific functions. One of these rapidly evolving factors is named TRIM52. We discovered that TRIM52 makes sure that human genetic material -DNA- is replicated correctly, and that cells in which TRIM52 is experimentally removed, can no longer multiply correctly. Interestingly, we found that while cells constantly produce TRIM52, it gets almost immediately degraded. This has raised the question as to why cells spend a lot of energy producing something that gets almost immediately degraded. This project aims to identify the specific cellular pathways that help replicate our DNA, that are controlled by TRIM52, and how. Moreover, the project aims to elucidate how cells rapidly degrade TRIM52, and why this is important for its cellular function. In the long term, results from this s tudy will contribute to our understanding of the strategies that have evolved in humans to support our complex bodies, systems that prevent damage to our genetic material, and consequently prevent cancer.

A human-specific protein guards our DNA, and cells destroy it almost as fast as they make it. Every cell contains thousands of proteins, each with a specific job. To stay healthy, cells carefully control protein levels by tagging surplus proteins with a molecular label called ubiquitin, sending them to the proteasome - a cellular recycling machine - for destruction. When this system fails, diseases including cancer can result. Our research focused on a protein called TRIM52, which presented two puzzles from the start. The first is evolutionary: TRIM52 is present in humans and other primates, where it has been actively shaped by natural selection, but has been lost in many other mammals. Proteins not conserved across species are typically specialized or dispensable. The second puzzle is stability: TRIM52 is destroyed so rapidly - half-life of just three to four minutes - that it is one of the most unstable proteins in the human body. Both puzzles deepened when we discovered TRIM52's function. Rather than playing a niche role, it is involved in protecting our DNA. When cells copy their DNA, a protein called Topoisomerase 2 helps untangle DNA strands but can become stuck, creating damage. TRIM52 helps resolve these blockages. Cells without TRIM52 accumulated more DNA damage and activated emergency signals halting cell division - a core quality control function, making it all the more striking that most other mammals appear to manage without it. Consistently, TRIM52 is elevated in several cancers, suggesting tumor cells depend on it for survival. We also identified three large enzymes - BIRC6, HUWE1, and UBR4 - that cooperate to label TRIM52 with ubiquitin and send it for recycling, and reconstructed this process step by step in a test tube with purified proteins. These findings raise a fascinating question guiding our future work: why did primates evolve a dedicated protein for a DNA quality control function that other mammals manage without? The answer may reveal something fundamental about how human cells handle DNA damage - and what that means for disease.