Academic Staff > M.S.Y. Huen

Michael Shing-Yan Huen (禤承恩)
Assistant Professor
B.Sc., M.Phil. (HKUST), Ph.D. (HKU)

Department of Anatomy and Centre for Cancer Research
L1-46, Laboratory Block
Faculty of Medicine Building
21 Sassoon Road, Hong Kong

Anatomy Office: (852) 3917-6868  (voice)
Anatomy Office: (852) 2817-0857 (fax)


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Education / Training

  • BSc, The Hong Kong University of Science and Technology, Hong Kong (1997-2000)
  • MPhil, The Hong Kong University of Science and Technology, Hong Kong (2000-2002)
  • PhD, The University of Hong Kong, Hong Kong (2002-2006)
  • Postdoctoral Research Fellow, Department of Radiation Oncology, Mayo Clinic, Minnesota, USA (2006)
  • Anna Fuller Fund Fellow, Department of Therapeutic Radiology, Yale University, Connecticut, USA (2007-2009)

Personal Webpage

Other Affiliations

  • Member, Centre for Cancer Research, The University of Hong Kong
  • Member, State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong
  • Senior Visiting Scholar, State Key Laboratory of Genetic Engineering, Fudan University

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Research Interests

  • DNA Damage Signal Transduction
  • Histone ubiquitylation
  • BRCA1-dependent DNA Damage Responses
  • Homologous Recombination DNA Repair
  • Fanconi Anemia

Research Description

Mammalian cells employ a collection of “DNA Damage Responses”(DDRs) to protect and maintain genome stability. These DDRs include cell-cycle checkpoints and DNA repair mechanisms. As one can imagine, when these protective mechanisms go awry, cells accumulate mutagenic damage, and become vulnerable to genome instability and neoplastic transformation.

My research aims to define the molecular regulations of these DDRs. The ultimate goal is to translate this knowledge to isolate better druggable targets and to develop more accurate and sensitive biomarkers for genome instability-associated syndromes. It is note-worthy to mention that genetic inactivation of DDRs not only contributes to cancer predisposition, but strikingly and unfortunately, individuals that inherit DDR-targeting mutations also manifest a variety of developmental deficits, including those that compromise neuromotor skills. Because of these reasons, I see an urgent need to understand how cells respond to genotoxic stress, and perhaps more specifically, how cells circumvent the deleterious effects of DNA damage, which may otherwise jeopardise the survival or quality of life of affected individuals. In addition, because current cancer chemotherapeutic agents are often themselves genotoxic compounds, it is important to understand how cancerous cells may respond differentially to these chemicals, such that maximal therapeutic potentials can be achieved at the bedside

One of my current research focuses centers on what is commonly referred to as the DNA damage-signaling cascade. This signaling cascade, activated by as little as one single DNA double-strand break (DSB), is instrumental in transducing DNA damage signals that culminate in the coordinated execution of the collection of DDRs. In particular, we have been very interested in studying how the ubiquitin machineries modify damaged chromosomes to sequester DNA damage mediator and repair proteins for effective checkpoint control and DNA repair. We have studied a number of positive regulators of this ubiquitin-dependent DNA damage-signaling pathway, and have more recently begun to look at how this pathway may be negatively regulated. While it is easy to appreciate the need to sequester DNA repair machineries at sites of DSBs, we recognise equal importance in ensuring that DNA-modifying activities do not excessively accumulate, especially at otherwise intact chromosomal loci. How then do cells restrict DNA damage-signaling to the vicinity of DSBs? We believe that cells have evolved strategies to suppress unscheduled or excessive accumulation of DNA damage mediator and repair proteins, and we are currently investigating how the functionalities of negative regulators of the DNA damage-signaling pathway may be coupled to cell proliferation and DNA repair.

Using breast and ovarian cancers as model systems, we have also a keen interest in understanding how the BRCA1-BRCA2 protein network suppresses human tumorigenesis. Mutations of BRCA proteins predispose individuals to early development of breast and ovarian cancers. However, mechanistically how the BRCA proteins suppress tumorigenesis has been a long-standing question. Built upon our previous studies that identified the Fanconi anemia protein PALB2 as the bridging factor of the two BRCA tumor suppressors, we are currently exploring the molecular regulation of the BRCA1-PALB2-BRCA2 axis in genome stability maintenance.

Research Grants (as Principal Investigator)

  • RGC-General Research Fund 2011/12 - Molecular and functional characterisation of USP34, a ubiquitin specific peptidase involved in the DNA damage response (Funded: HKD1,010,000)
  • RGC-Early Career Scheme 2012/13 - Role of ATM signaling in PALB2-dependent homologous recombination DNA repair (Funded: HKD1,846,200)
  • NSFC-RGC 2013/14 - Study role of PCNA-binding protein TRAIP in replicative stress responses and tumor suppression (Funded: HKD1,123,616)
  • RGC-General Research Fund 2014/15 - Examining negative regulatory mechanisms of DNA damage signal transduction & their impact on maintenance of genome stability (Funded: HKD1,131,600)

Awards and Honors

  • Early Career Award 2012-13, Research Grant Council , Hong Kong

Editorship and Professional Membership

  • Academic Editor, PLOS ONE
  • F1000 Specialist, Faculty of 1000

Lab Personnel

  • Jie CHEN (PhD student; 2012-)
  • Yingying GUO (PhD student; 2012-)
  • Wanjuan FENG (Postdoctoral Fellow; 2012-)
  • Alice H.M. NG (PhD student; 2013-)
  • Wilson C.Y. LAU (Postdoctoral Fellow; 2014-)
  • Liwei AN (PhD student; 2014-)

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Selected Publications

  1. Sy SM, Jiang J, O WS, Deng Y, Huen MS. The Ubiquitin Specific Protease USP34 promotes ubiquitin signaling at DNA double-strand breaks. Nucleic Acids Res 2013; 41(18):8572-80.
    This paper identifies USP34 as a new regulator of signaling events at DNA double-strand breaks (DSBs). We showed that USP34 stabilises the RIDDLE syndrome protein RNF168, thereby reinforcing chromatin ubiquitylation surrounding DSBs for effective assembly of DNA damage signaling and repair proteins, including 53BP1 and BRCA1. We proposed that USP34 plays a role in the feed-forward loop of ubiquitin-signaling at DSBs.

  2. Chen J, Feng W, Jiang J, Deng Y, Huen MS. Ring Finger Protein RNF169 antagonizes the ubiquitin-dependent signaling cascade at sites of DNA damage. J Biol Chem 2012; 278(33):27715-22.
    This paper identifies RNF169 as a negative regulator of signaling events stemming from DNA double-strand breaks (DSBs).  We found that RNF169, via its ubiquitin-interacting motif, competes for DSB-associated ubiquitin structures and displaces accumulation of DNA damage signaling and repair factors 53BP1 and BRCA1. We proposed that RNF169 suppresses unscheduled activation of DNA damage responses. Similar findings were independently reported by Durocher Lab and Mailand Lab.

  3. Lok GT, Sy SM, Dong S, Ching YP, Tsao SW, Thomson TM, Huen MS. Differential regulation of RNF8-mediated Lys48- and Lys63-based poly-ubiquitylation. Nucleic Acids Res 2012; 40(1): 196-205.
    This paper reported a RING-dependent regulatory mechanism behind topology-specific ubiquitin polymerisation. We provided evidence to show that lys48- and lys63-based polyubiquitylating activities can be decoupled in the E3 ubiquitin ligase RNF8 via selective binding to E2 conjugative enzymes UBCH8 and UBC13, respectively.

  4. Sy SM, Jiang J, Dong S, Lok GT, Wu J, Cai H, Yeung ES, Huang J, Chen J, Deng Y, Huen MS. Critical roles of Ring Finger Protein RNF8 in replication stress responses. J Biol Chem 2011; 286(25): 22355-22361.
    This paper reported a specific role for the E3 ubiquitin ligase RNF8 in replicative stress responses. We found that RNF8, but not its immediate downstream factor RNF168, is strictly required for cell recovery from replicative stress. We proposed that limited DSB ubiquitylation displays a bias for DNA repair via homologous recombination.

  5. Huen MS, Huang J, Leung JW, Sy SM, Leung KM, Ching YP, Tsao SW, Chen J. Regulation of chromatin architecture by the PWWP domain-containing DNA damage responsive factor EXPAND1/MUM1. Mol Cell 2010; 37:1-11. (Recommended by F1000Prime)
    This paper identifies MUM1 (hereafter renamed as EXPAND1) as a new effector of DNA damage signaling pathway. We provided evidence to show that EXPAND1, endowed with nucleosome-interacting properties, interacts with the tumor suppressor 53BP1, is recruited to DNA double-strand breaks (DSBs), and facilitates DNA repair by modulating chromatin architecture.

  6. Santos MA, Huen MS, Jankovic M, Chen H, Lopez-Contreras A, Klein IA, Wong N, Barbancho JL, Fernandez-Capetillo O, Nussenzweig MC, Chen J, Nussenzweig A. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8. J Exp Med 2010; 207(5):973-81.
    This paper reported important roles of the E3 ubiquitin ligase RNF8 in class switching and meiosis in mice. Similar to its function in promoting 53BP1 accumulation at DNA double-strand breaks (DSBs), we found that RNF8 is required for proficient class switching recombination, and that inactivation of RNF8 resulted in accumulation of unresolved immunoglobulin heavy chain-associated DSBs.

  7. Sy SM, Huen MS, Chen J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. PNAS 2009; 106(17):7155-60. (Highlighted in Science – “Complicated supercomplex”)
    This paper identifies the Fanconi anemia protein PALB2 as the bridging protein for the BRCA1 and BRCA2 tumor suppressors. While the BRCA proteins share common roles in suppressing human tumorigenesis, exactly how the two proteins functionally interact has been a long-standing question. By purifying PALB2-associated proteins, we found that PALB2 interacted with both BRCA1 and BRCA2. We provided evidence to show that the BRCA1-PALB2-BRCA2 complex promotes homologous recombination and cell resistance to DNA damage. Similar findings were independent reported by Yu Lab and Andreassen Lab.

  8. Huang J, Huen MS, Kim H, Leung CC, Glover JN, Yu X, Chen J. RAD18 transmits DNA damage signaling to elicit homologous recombination repair. Nat Cell Biol 2009; 11(5):592-603. (Recommended by F1000Prime)
    This paper identifies a new regulatory mechanism for RAD18-dependent DNA repair. We found that RAD18 is endowed with ubiquitin-binding properties and is targeted to DNA double-strand breaks (DSBs) in an RNF8-dependent manner. We also showed that RAD18 promoted DNA repair by facilitating the accumulation of RAD51 paralogues to the vicinity of DSBs.

  9. Huen MS, Huang J, Yuan J, Yamamoto M, Akira S, Ashley C, Xiao W, Chen J. Non-canonical E2 variant-independent function of UBC13 in promoting checkpoint protein assembly. Mol Cell Biol. 2008;28(19):6104-12.
    This paper reports an unanticipated role of the E2 ubiquitin enzyme UBC13 in catalysing ubiquitin reactions. By pairing with the E3 ubiquitin ligase RNF8, UBC13 plays key roles in DNA damage signal transduction. We found surprisingly that this function of UBC13 is independent of its heterodimer pairs MMS2 and UEV1A. Using a series of chimeric proteins, we also showed that RNF8, via its RING domain, targets UBC13 to DNA double-strand breaks (DSBs) and is sufficient in promoting DSB association of 53BP1.

  10. Huen MS, Grant R, Manke I, Minn K, Yu X, Yaffe MB, Chen J. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 2007; 131(5):901-14. (Recommended by F1000Prime; Highlighted in Nat Rev Mol Cell Bio – DNA damage: Conducting repair and in Nat Struct Mol Biol – DNA damage: ubiquitin marks the spot)
    This paper identifies the E3 ubiquitin ligase RNF8 as a key factor in propagating DNA damage signals for effective assembly of checkpoint and DNA repair proteins at DNA double-strand breaks (DSBs). We found that RNF8, via its phospho peptide-interacting FHA domain, is targeted to DSBs where it promotes non-degradative ubiquitin polymerization to anchor DNA damage signaling and repair proteins, including 53BP1 and RAP80-BRCA1. Similar findings were reported by Durocher Lab, Lukas Lab and Elledge Lab.

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