Professor Michael Huen Shing-yan — DNA Repair as a Pathway to Fighting Disease | 禤承恩教授 — 修復DNA 擊退疾病

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.

Biography

Professor Michael Huen received his doctorate degree from HKUMed in 2006, and trained with Professor Junjie Chen as Postdoctoral Research Fellow at Mayo Clinic (Minnesota, USA) and later at Yale University (Connecticut, USA). He joined the former Department of Anatomy, HKUMed in 2009 and was promoted to Professor of School of Biomedical Sciences in 2019. Professor Huen is also currently Assistant Dean (Innovation and Technology) of HKUMed.

Professor Huen’s main research focus is on DNA damage detection and repair control. His research team employs multi-disciplinary approaches to identify key players and events that drive genome integrity protection. Aside from its direct implications in human health and disease, insight in the regulation of DNA repair also contributes to the operational framework of emerging methodologies in gene-editing and gene replacement therapies in the biotechnology industry.

(This article was originally published in Medical Faculty News)

我們每日都會遇到破壞自身DNA的媒介，例如陽光和煙草煙霧。其實細胞本身已具備一套修復損傷的機制，但是這套機制有時不堪重負，從而導致發育缺陷、提早衰老，甚至可致癌。生物醫學學院的禤承恩教授多年來致力研究，揭示DNA 損傷訊號傳遞和修復過程中涉及的分子機制。

禤教授指出：「我們的研究重點在於識別DNA修復機制背後的關鍵分子元素，以了解細胞如何維護基因組的完整性，這有助我們對由於缺乏DNA修復能力所引起的疾病，作出更準確的診斷和評估。」這些研究亦將有助於發展嶄新的抗癌治療方法。

禤教授近期其中一項發現是成功複製RNF169基因。RNF169與DNA損傷反應蛋白有關，對於準確無誤地修復受損DNA方面至關重要；如果要RNF169運作正常，其蛋白水平必須受到嚴格調控。在實驗室的觀察裡，人體癌細胞中 RNF169的蛋白水平，其調控能力確是比較差。有關發現指引了癌症藥物的研究新目標，以及健康生活和延長壽命的新想法。

此外，禤教授和他的團隊正嘗試破解DNA修復機制與基因表達（又稱轉錄）的相互作用。在修復過程中，基因表達必須暫時受抑制，以免令染色體受損並引致異常。研究團隊正進行篩選，以找出與保護基因組完整性有關的新元素。他們透過 結合矩陣基因編輯CRISPR篩選和高通量顯微鏡分析技術，找出新DNA修復因子。這些先進的方法將有助他們能夠高效及有系統性地識別出可以維持基因組穩定性的宿主元素。

禤教授和在中國內地的合作伙伴，亦已取得國家自然科學基金委員會及香港研究資助局聯合科研基金的資助，利用經基因改造的小鼠模型研究新DNA修復基因的腫瘤抑制特性，提供有關抑制腫瘤和細胞正常生長的重要啟示。

禤教授表示：「透過鑑定DNA損傷反應蛋白的基本組成部分，以及揭示相關蛋白網絡的緊密聯繫，我們期望能發掘嶄新且可應用的檢測方法，治療甚至杜絕與DNA損傷反應失 調有關的人類疾病。」

身兼港大醫學院助理院長（創新及科技）的禤教授在DNA修復方面的成績廣受肯定，同時亦讓他獲選擔任國際知名、以頂尖領先研究為研討主題的會議 Gordon Research Conference的聯席主席。

簡歷

禤承恩教授於2006年獲頒港大醫學院博士學位，之後遠赴美國明尼蘇達州Mayo Clinic及在康涅狄格州的耶魯大學進行博士後研究。2009年他加入港大醫學院的解剖學系（前稱），並於2019年晉升為生物醫學學院教授。禤教授目前同時為港大醫學院助理院長（創新及科技）。

禤教授的主要研究重點是DNA損傷的檢測和修復機制，其研究團隊採用跨學科的方法，找出與保護基因組完整性有關的新元素。他的研究除了對人類健康和疾病有直接影響，對於修復DNA機制的深入探討，在建立生物科技領域中的基因編輯和基因替代療法等新興研究方法的運作框架,尤其貢獻良多。

(原文刊登於港大醫學院 Medical Faculty News)