Medical Faculty News v25i1

DNA Repair as a Pathway to Fighting Disease Every day, we encounter agents that can damage our DNA, such as sunlight and tobacco smoke. Our cells have evolved mechanisms to fix that damage, but sometimes this system is overwhelmed, leading to developmental deficits, premature ageing and cancer. Professor Michael Huen Shing-yan of School of Biomedical Sciences has been uncovering the molecular mechanisms involved in DNA damage signalling and repair processes. “My focus is on identifying the molecular determinants behind DNA repair so we can understand how cells protect our genetic material. This will improve our ability to diagnose and assess diseases that arise from DNA repair deficiencies,” he said. This work can also lead to the development of new anti-cancer therapies. One recent achievement from the Huen Laboratory has been the discovery of the gene RNF169, which they showed encodes a DNA damage response protein that not only is important for error-free DNA repair but that its protein level must be tightly regulated for it to function properly. The latter was an important confirmation of observations that RNF169 is poorly regulated in human cancers. The findings highlight new targets for cancer drugs and new ideas on healthy living and longevity. Professor Huen has recently shifted his interest to decipher the interplay of DNA repair with gene expression (also known as transcription). Gene expression must be temporarily inhibited during the repair process so as not to damage the chromosome and cause aberrations. The research team has performed genetic and chemical screens to seek out new factors involved in protecting genome integrity. For instance, they have begun applying arrayed CRISPR screens coupled with high-content microscopy analyses to find new DNA repair factors. These advanced methodologies will enable them to do high-throughput, systematic identification of host factors that are important in maintaining genome stability. Professor Huen and his Mainland collaborators have also received research funds from National Natural Science Foundation of China (NSFC) and Research Grants Council of Hong Kong (RGC) Joint Research Scheme to generate and study the tumour-suppressive properties of new DNA repair genes in mice, using genetically engineered mouse models. This is expected to provide insights on tumour suppression and normal cell development. “By identifying the basic components and unravelling the intimate connections of the DNA damage response [DDR] protein network, we hope to uncover novel and feasible means of detecting, treating and eradicating human diseases associated with DDR dysregulation,” he said. Professor Huen’s contribution and recognition in the DNA repair field led to his election as co-chair of Gordon Research Conference on Genomic Instability, a series of prestigious international meetings on frontier research. He is also HKUMed’s Assistant Dean for Innovation and Technology. By identifying the basic components and unravelling the intimate connections of the DNA damage response [DDR] protein network, we hope to uncover novel and feasible means of detecting, treating and eradicating human diseases associated with DDR dysregulation. 14 Feature