
Targeting DNA bridges: HKU Biologists Uncover key to preserve genome integrity Enhancing the understanding of cancer development
A research team led by Dr Gary Ying Wai CHAN from the School of Biological Sciences at The University of Hong Kong (HKU), has uncovered a new mechanism that ensures correct DNA segregation in cell division, where improper cell division will lead to the development of cancer. The team's findings, published in the journal Cell Reports, focus on the roles of two proteins, RIF1 and protein phosphatase 1 (PP1), in resolving ultrafine DNA bridges. These bridges are formed when sister chromatids are connected by DNA joint molecules during mitosis. If these DNA bridges cannot be resolved or removed properly, they will eventually break and cause DNA damage in the daughter cells, which can lead to the development of cancer cells. The process of Mitosis A human life begins with a single cell – the fertilised egg. This single cell needs to replicate and divide into approximately 37 trillion cells. The process by which a cell replicates its DNA then equally segregates into two identical cells is known as mitosis, which is a vital process for growth and replacing worn out cells. However, equal segregation of DNA is one of the most challenging tasks in mitosis. Our DNA is organised into 23 pairs of chromosomes, each of which is replicated into two sister chromatids. During mitosis, these sister chromatids are separated into two identical daughter cells. They are often connected by DNA joint molecules, which can form long fine DNA threads known as ultrafine DNA bridges when the two sister chromatids are separating under a pulling force. If these DNA bridges cannot be resolved or removed properly, they will eventually break, causing damage in the daughter cells. In a worst-case scenario, this DNA damage can potentially lead to the development of cancer. To elucidate the detailed mechanism of how cells resolve the DNA bridges, the team led by Dr Gary Ying Wai Chan uncovered the roles of two proteins, RIF1 and protein phosphatase 1 (PP1) in regulating the resolution of ultrafine DNA bridges. The role of RIF1 and PP1 in resolving DNA bridges In 2007, two research groups led by Professor Erich NIGG and Professor Ian HICKSON discovered the existence of ultrafine DNA bridges by identifying the first two ultrafine bridge-binding proteins, PICH and BLM. Later on, RIF1 was also identified as a bridge-binding protein. It is known that PICH is the first protein recognising the DNA bridges, then it recruits BLM and RIF1 to ultrafine DNA bridges; however, the exact mechanism by which these bridge-binding proteins work to resolve the bridges remains unclear. To understand the role of RIF1 in resolving DNA bridges, the research team employed a revolutionary genome editing technology, the CRISPR/Cas9, to deplete RIF1 in a cell model during mitosis. During which, the team found that loss of RIF1 leads to increased formation of DNA damage and micronuclei due to breakage of ultrafine DNA bridges, as our data suggest that RIF1 plays a crucial role in preventing double-stranded DNA bridges from converting into single-stranded DNA, which is more susceptible to breakage. RIF1 was found to achieve this by recruiting PP1, a protein phosphatase, which reduces the interaction between BLM and PICH and thereby reduces the amount of BLM on the bridges, which the team discovered that is responsible for unwinding the bridge DNA to single-stranded DNA. Finally, the double-stranded DNA bridges protected by RIF1-PP1 are believed to be resolved by another enzyme known as topoisomerase IIα, which could mediate double-stranded DNA decatenation to ensure proper DNA segregation. This research not only sheds light on the novel regulatory mechanism by which RIF1-PP1 facilitates the resolution of DNA bridges, but also reveals how ultrafine DNA bridges can induce DNA damage and genome instability if they are not properly resolved. The findings suggest that DNA bridge-binding proteins may serve as potential therapeutic targets for the development of anticancer drugs, as DNA bridges are considered a source of genome instability that drives tumorigenesis. ‘The discovery that RIF1 recruits PP1 to the bridges is the first step in understanding how the resolution of ultrafine DNA bridges is regulated by protein phosphorylation/dephosphorylation,’ said Dr Gary CHAN. ‘The next step is to identify the target substrates of the RIF1-PP1 complex, which can advance our understanding of how different bridge-binding proteins interact with each other and may lead to the identification of new therapeutic targets for cancer.’ The journal paper, entitled ‘RIF1 Suppresses the Formation of Single-Stranded Ultrafine Anaphase Bridges via Protein Phosphatase 1’, can be found here. Click here to learn more about the work of Dr Ying Wai Chan and his research team.
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Alumni Series - Tracing the Roots of Food with Stable Isotope Analysis
Food has always been fundamental to human life, connecting people to their roots, culture, and memories. As globalisation increases and food fraudulent concerns mount, tracing the journey of food from farm to table has become increasingly important. Faced with these challenges, two visionary PhD graduates from The School of Biological Sciences founded IsoFoodtrace, a company utilising stable isotope analysis, a food traceability technology, to provide a reliable and efficient platform for tracking food products’ origin and journey. IsoFoodtrace verifies food product attributes and labels, enabling unparalleled assurance in global food systems. By directly testing end products, their fast and cost-efficient methods allow consumers to know exactly what they buy. Let us explore the pioneering journeys of these young entrepreneurs driving unprecedented assurance in our food systems. Dr Colin Luk and Dr David Baker. Meeting during their PhD studies in 2014, Inga CONTI-JERPE investigated coral nutrition using stable isotope analysis while Colin LUK studied forest recovery using Arthropods indicators. At that point, Colin had over ten years of F&B experience with concerns about food origin. He recalled, ‘I discussed using stable isotope analysis to detect food fraud with Inga, and we both think it’s doable. At the same time, HKU iDendron had just initiated a start-up SEED program while Science Park offered a 100K start-up grant—it seemed a good opportunity for us to build a start-up.’ With the support of Dr David BAKER, the Director of HKU Conservative Forensic Laboratory, and the consultation from Dr Jetty LEE, the Programme Director of the HKU MSc Food Industry: Management & Marketing, they piloted testing supermarket wild salmon and wrote a business proposal for funding, enabling them to launch IsoFoodtrace, a real business tackling food fraud. Empowering Consumers to Make Informed Choices Dr Colin Luk at the Stable Isotope Laboratory of HKU Stable isotope ratios vary with food attributes like farming practices, feed, and origin. For example, wild salmon has more 15N (Nitrogen) than farmed, and cattle feed diets (grass vs grain) affect 13C (Carbon) ratios. Using Stable Isotope Ratio Mass Spectrometry, foods are chemically analysed and isotopes measured. Once the stable isotope signatures have been detected, they are then compared against a reference database; hence, the origin and composition of a food sample can be determined. This cutting-edge technology can ensure food safety and authenticity, giving customers peace of mind.. In just two years, IsoFoodtrace has grown to a team of 11. In the long term, it aims to build a global food stable isotope database enabling verification of production and origin claims. Colin said, ‘We aim not only to battle fraudulent claims of food quality but also to contribute to better food safety and sustainability by allowing businesses and consumers to make more informed purchases.’ Through their innovative approach to food tracing, they have revealed the complex processes involved in food production and distribution. Though now relocated to the US, Inga continues working with Colin to grow the business, she said, ‘Food safety is of paramount importance in today's globalised food systems. By tracing the roots of food, I hope we can eventually empower consumers to make informed choices and holds businesses accountable for authentic claims.’ As consumers, we can all play a role in supporting their efforts by seeking out products that have been verified and demanding greater transparency in the food industry. By doing so, we can help to build a safer and more sustainable food system for all. Dr Colin Chung-lim LUK PhD in Biological Sciences Project Development Lead@isoFoodtrace Dr Inga E. CONTI-JERPE Scientific Development Lead@isoFoodtrace Biological Researcher at University of California, Berkely
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