Ian David Hickson

Primary fields of research

Background The chromosomes in all living organisms are under constant attack from reactive chemical species that can damage the structural integrity of the DNA. All cells, therefore, devote considerable energy to both preventing and repairing DNA structural abnormalities. Despite this, thousands of DNA lesions still arise daily in each human cell. The majority of these lesions pose no threat to cell viability, but their cumulative effect in a long-lived species influences lifespan and the incidence of age-related diseases such as cancer and neurodegeneration.
Our laboratory investigates the biochemical, molecular and cell biological functions of DNA repair factors in eukaryotic cells and how these factors act to maintain chromosome stability. In particular, we focus on those genes that, when defective, give rise to disorders in humans associated with the premature onset of aging and/or age-associated diseases such as cancer.

In recent years, a major focus has been on characterization of BLM, the protein defective in Bloom's syndrome, a disorder associated with an elevated incidence of cancers of all types. The BLM gene encodes a DNA helicase of the RecQ family, which has important roles in DNA replication and repair via the homologous recombination pathway. We combine analysis of the biochemical properties of BLM with both studies in human cells lacking BLM and studies of SGS1, the budding yeast ortholog of BLM.
Following our recent move from the University of Oxford to the Center for Healthy Aging in the ICMM, we have re-aligned many of our studies to focus on the aging process in humans. Fortunately, chromosome maintenance pathways, including those involving RecQ helicases, are known to impact directly on the rate of human aging. This can be seen most strikingly in human disorders associated with accelerated aging, such as Werner's syndrome (WS). In WS, loss of the RecQ helicase encoded by the WRN gene leads to early onset, multi-organ aging.

Current research

(i) Biochemical analysis of RecQ helicases We use purified recombinant proteins and defined DNA substrates to investigate the functions of RecQ helicases and their partner proteins in DNA replication and homologous recombination repair. For example, we discovered and re-constituted biochemically a pathway for processing recombination intermediates that requires BLM. This is a process called Holliday junction dissolution.

Model for the role of BLM in the dissolution of double Holliday junctions

ii) Factors required for the regulation of homologous recombination We are using molecular genetics and biochemistry to characterize factors, such as FBH1, that regulate the efficiency of homologous recombination repair.

(iii) Cellular responses to DNA damage We are analyzing the role of selected post-translational modifications of proteins in regulating the cellular response to DNA damage and other stresses occurring during DNA replication.

 

An example of a late anaphase cell with a long anaphase bridge stained with BLM (red). DNA is in blue.

(iv) Characterization of a novel class of anaphase bridge structure. Through analyzing the localization of BLM, we identified a class of ultra-fine anaphase bridges that link sister chromatids at either centromeres or fragile site loci. This latter class (see photo) have foci for the FANCD2 protein at their termini. FANCD2 is a protein required for the so-called Fanconi anaemia pathway for DNA repair. We are investigating the source of these bridges, and how BLM helps to resolve them. BLM acts alongside a SNF2 family protein called PICH, which we are analyzing biochemically and functionally through the use of PICH-depleted human cells and chicken DT-40 cell knock-out mutants. We are also investigating how phosphorylation of BLM and PICH in mitosis regulates their function.

(v) Use of yeast to study chromosome maintenance pathways Because the pathways we analyze are highly conserved, we can use budding yeast as a model organism to conduct detailed genetic characterization of the BLM ortholog, Sgs1. These studies also enable the use of techniques, such as 2-dimensional DNA replication gel analysis and genome-wide screens to be conducted. For example, we have created a system for site-specific blockade of DNA replication, and are analyzing proteins recruited to the site of blockade and the mechanism by which the blockade is overcome.

Funding Sources
The Danish National Research Foundation, The Nordea Foundation Center for Healthy Aging, The European Research Council, The European Union and The Danish Council for Independent Research (Medical Sciences and Natural Sciences).

Collaborators
Drs Guillermo Montoya and Niels Mailand, Center for Protein Research, University of Copenhagen, Denmark.
Dr. Keith Caldecott, Genome Damage and Stability Centre, University of Sussex, UK.
Dr. Chuna Choudhary, Center for Protein Research, University of Copenhagen, Denmark.
Dr Michael Lisby, University of Copenhagen, Denmark.
Drs Claudia and Jiri Lukas, Center for Protein Research, University of Copenhagen, Denmark.
Dr. Erich Nigg, Biocenter, Basel, Switzerland.
Drs Erwin Peterman and Gijs Wuite, Free University of Amsterdam, The Netherlands.
Dr. Nicolas Thomä, FMI, Basel, Switzerland.
Dr Alessandro Vindigni, St. Louis University, USA.
Dr Stephen West, Cancer Research UK, London Research Institute, UK
Dr. Lily Hui-Ching Wang, National Tsing Hua University, Taiwan
Dr Shunichi Takeda, Kyoto University, Kyoto, Japan
Drs  Songmin Ying and Huahao Shen, Zhejiang University, China

CV

CURRICULUM VITAE
Ian D. Hickson PhD FMedSci FRS
Personal Details:
Full Name: Ian David Hickson
Date of Birth: 19th August, 1957
Citizenship: British (permanent resident status in Denmark and the EU)
Tel: +45-35326738 (office) 51297877 (mobile)
Email: [email protected]
Curriculum Vitae Ian D. Hickson July, 2018

Educational qualifications:
Doctor of Philosophy, ICI CASE Studentship with Prof. P.T.Emmerson and Dr. K. Powell, Universities of Newcastle and Leicester /ICI Laboratories Billingham/Alderley Park 1982.

Present position:
Director of the DNRF Center for Chromosome Stability, Theme Leader in the Center for Healthy Aging and Professor of Molecular Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Denmark.

Relevant previous posts:
1983-1989 University Lecturer (Endowed Post)
Cancer Research Unit, University of Newcastle upon Tyne Medical School, UK
1989-1999 ICRF Senior Scientist and then promoted to Principal Scientist
Department of Medical Oncology, University of Oxford, Weatherall Institute
of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
1994-1999 University Research Lecturer, University of Oxford, UK
1999-2009 Deputy Director, Cancer Research UK Oxford Cancer Centre, University of
Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
1999-2010 Professor of Molecular Oncology, Weatherall Institute of Molecular Medicine,
University of Oxford, Oxford, OX3 9DS, UK, 2010.

Personal awards and professional responsibilities:
1997-2001 Member of the Cancer Research Campaign Project Grants Committee
1997-2002 Member of the Cancer Research UK Research and Management Group
1999-2002 Consultant to Aventis (Rhone-Poulenc Rorer) France
1999-2004 Chairman of the Cancer Research UK Library Committee
2000-2010 Member of the Weatherall Institute of Molecular Medicine Management Group
2001-2002 Deputy Chairman, Cancer Research Campaign Project Grants Committee
2001-date Editorial Board Member of DNA Repair and Oncology Research
2002-2009 Deputy Chairman, Cancer Research UK Projects Committee
2003-2004 Chairman of the Cancer Research UK Studentships Committee
2003-2009 Scientific Advisory Board Member of The Danish Centre for Molecular Gerontology, Aarhus, Denmark
2005-2009 Consultant to UCB/Celltech
2009-2016 Scientific Advisory Panel member of Nature Communications
2010 Elected Fellow of the Academy of Medical Sciences (UK)
2010-2015 Organizer of a cross-faculty Chromosome Biology Interest Group
2010 Elected Fellow of the Royal Society (UK)
2010 Elected Member of the ‘Faculty of 1000’ in Biology
2011 Elected Member of The European Molecular Biology Organization (EMBO)
2012-date Editorial Board Member of F1000 Research
2012-date Organizer of the Departmental Seminar Program, University of Copenhagen
2012 Awarded an Advanced Grant from the European Research Council (ERC)
2013 Recipient of a Federation of European Biochemical Societies (FEBS)
National Lecturer Award (presented at the annual society meeting in Hungary)
2013-2016 Royal Society Research Grant Board Member (Biological Science)
2013-2015 ERC Consolidator Grants Evaluation Panel Member
2014-date External Advisory Board Member of the UK Prostate Cancer Research Centre
2015-date Qiushi Guest Professor at Zhejiang University, Hangzhou, China
2015-2018 Wellcome Trust (UK) Scientific Interview Panel Member
2017-date Member of the advisory board of the Center for Integrative Microscopy, University of Copenhagen
2017-date Consultant to Ono Pharma (UK)

University teaching:
I lecture on Masters and PhD courses in both the Health and Medical Sciences and the Science Facilities of the University of Copenhagen. I supervise clinical and non-clinical trainees in order for them to obtain a postgraduate research qualification. I have acted as the primary supervisor of the following PhD students:
1989-2018 PhD students: Stella Davies, Paul Hoban, Craig Robson, Sally Davies, Andrew Fry, Daniel Hochhauser, Lisa Walker, Nicholas Wells, Gil Barzilay, Christopher Tomkins, Richard Isaacs, Dominic Rothwell, Xiaoqi Wang, Ines Sandri, Ronjon Chakraverty, Julia Karow, Jeremy Braybrooke, Adele Goodwin, Thomas Oakley, Chit-Fang Cheok, Srinivasan Madhusudan, Nicola Levitt, Hien Ping Ngo, Wai-Kit Chu and Kok Lung Chan, Miranda Payne, Phillip North, Thomas Ashton, Giang Nguyen, Sara Bursomanno, Christian Nielsen, Nicolai Larsen, Ganesha Pitchai, Signe Jørgensen, Ozgun Ozer and Aiste Aleliunaite.
Current PhD students: Andres Bueno Venegas and Khaled Almutairi.

Destination of selected trainees from my laboratory:
1) Paul Watt, Group leader, University of Western Australia. Founder and Company Scientific Officer at Phylogica Limited, Perth, Australia
2) Craig Robson, Professor of Cancer Studies, University of Newcastle upon Tyne, UK
3) Clive Stanway, Chief Scientific Officer, Imperial Cancer Research Technology (later CRT), London, UK
4) Julia Karow, Senior Editor, Genome Web, New York, USA
5) Leonard Wu, Group leader, Weatherall Institute of Molecular Medicine, University of Oxford, UK
6) Chit Fang Cheok, Group leader, IFOM-A*Star, Singapore
7) Andrew Fry, Professor, Department of Biochemistry, University of Leicester, UK
8) Csanad Bachrati, Reader, University of Lincoln, UK
9) Ji-Liang Li, Professor of Cancer Biology, University of Plymouth, UK
10) Songmin Ying, Professor, Zhejiang University School of Medicine, Hangzhou, China
11) Sheroy Minocherhomji, Senior Scientist and Group Leader, Amgen Corporation, San Francisco, USA
12) Ozgun Ozer, Postdoctoral Fellow with Prof. Jonathan Pines, Institute of Cancer Research, London, UK

Management and administrative experience:
As Deputy Director of the Cancer Research UK Oxford Cancer Centre, I represented the University Department of Medical Oncology and the Cancer Centre on several committees within the University and Cancer Research UK. I performed numerous management and administrative functions within the Department, including allocation of research space, control of research budgets and selection of staff at all levels, including group leaders. I was one of the 6-strong Management Group that was responsible for advising the Director on many aspects of the running of The Weatherall Institute of Molecular Medicine (WIMM).
Since moving to the University of Copenhagen, I have taken over the position of Theme Leader for Nordea Center for Healthy Aging. I also sit on the 6-strong Steering Committee of the Center. In March 2015, I became the Director of the Center for Chromosome Stability (CCS), a research center comprising 8 research teams, which is funded by a 65,000,000 DKK grant from the Danish National Research Foundation. In the CCS, I am responsible for the scientific direction of the CCS, as well as personnel and financial management.

Scientific reviewing:
Reviewer of grant applications for the Medical Research Council, Wellcome Trust, Cancer Research UK, the National Institutes of Health and National Science Foundation (USA), the Dutch Cancer Society, the Association for International Cancer Research.
Reviewer of papers for a broad cross-section of molecular biology and cancer journals; including, Cell, Nature, Science, Nature Genetics, Nature Cell Biology, Molecular Cell, EMBO J., British Journal of Cancer, Journal of Biological Chemistry, Cancer Research, Molecular and Cellular Biology, Proceedings of the National Academy of Science (USA).

Oral scientific presentations (by invitation) 2013 to date:
2013 Centre for Chromosome Stability, National University of Galway, Ireland.
2013 Joint Keystone Conferences on ‘DNA Replication and Recombination’ and ‘Genome Instability and DNA Repair’, Banff, Canada (Symposium Speaker).
2013 Department of Biochemistry, Masaryk University, Brno, Czech Republic.
2013 FEBS Lecture (Keynote Address) Hungarian Biochemical Society Conference, Siofok, Hungary.
2013 Department of Biochemistry and Molecular Biology, St Louis University, St Louis, USA.
2013 University of Chicago Comprehensive Cancer Center, Chicago, USA.
2013 3rd Nordforsk Meeting on ‘Chromatin, Transcription and Cancer’, Copenhagen, Denmark (Symposium Speaker).
2013 Gray Cancer Institute Symposium, Oxford, UK (Symposium Speaker).
2013 Faculty of Medicine, Zhejiang University, Hangzhou, China.
2013 Alliance of Healthy Aging Symposium, Groningen, The Netherlands (Symposium Speaker).
2013 Genome Damage and Repair Centre, University of Sussex, UK.
2014 American Association for Cancer Research Conference on ‘Cancer Susceptibility Syndromes’, San Diego, USA (Symposium Speaker).
2014 Abcam conference on ‘Mechanisms of Recombination’, Alicante, Spain (Symposium Speaker)
2014 5th Symposium of ‘Genome Damage and Repair’, Helsingør, Denmark (Symposium Speaker)
2014 Department of Biochemistry, University of Oxford, UK.
2014 Fusion Conference on ‘DNA Replication as a source of DNA damage: from molecules to human health’, Casablanca, Morocco (Organizer, Chair and Symposium Speaker).
2015 EU Consortium Workshop ‘DNA Damage Responses’, Amsterdam, The Netherlands (Chair and Invited Speaker).
2015 Zhejiang University School of Medicine, Hangzhou, China.
2015 Chengde University Medical School, Chengde, China.
2015 The 2015 IMB Symposium ‘DNA Repair and Genome Stability in a Chromatin Environment’, Mainz, Germany (Symposium Speaker).
2015 Tomas Lindahl Conference on DNA Repair, Oslo, Norway (Symposium Speaker).
2015 44th Annual Meeting of the European Environmental Mutagenesis and Genomics Society, Prague, Czech Republic (Keynote Speaker).
2015 Cold Spring Harbor Symposium on ‘Eukaryotic DNA Replication and Genome Maintenance’, New York, USA (Chair and Symposium Speaker).
2016 Abcam Conference on ‘Maintenance of Genome Stability’, Panama City, Panama (Symposium Speaker).
2016 99th Christian A. Herter Invited Lecture, New York University School of Medicine, USA.
2016 Abcam Conference on ‘Mechanisms of Genetic Recombination, Alicante, Spain (Symposium Speaker).
2016 Gordon Research Conference on ‘Mutagenesis and Genome Stability, Girona, Spain (Keynote Speaker and Session Chair).
2016 Mutation to Malignancy Symposium, University of Zurich, Switzerland (Symposium Speaker).
2016 Benzon Foundation Conference on ‘Genome Instability and Neurodegeneration’, Copenhagen, Denmark (Symposium Speaker, Session Chair and Co-Organizer).
2016 Institute of Molecular Biology, Mainz, Germany
2016 Zhejiang University School of Medicine, Hangzhou, China.
2017 Institute of Genetics and Molecular Medicine, University of Edinburgh, UK
2017 Cold Spring Harbor Annual Meeting (Symposium Speaker).
2017 FUSION Conference on ‘DNA replication as a source of DNA damage’, Rome, Italy (Co-organizer, Symposium Speaker and Chair).
2017 EMBO Workshop on ‘DNA topoisomerases’, Les Diablerets, Switzerland (Invited Speaker).
2017 EMBO Conference on ‘DNA damage responses’, Athens, Greece (Invited Speaker).
2017 Zhejiang University School of Medicine, Hangzhou, China.
2017 Workshop on ‘DNA replication stress and human disease’ Baeza, Spain (Invited Speaker).
2018 A*Star Research Institute, Singapore.
2018 St Vincent’s Institute, Melbourne, Australia.
2018 Lorne Genome Conference, Lorne, Australia (Symposium Speaker).
2018 Children’s Medical Research Institute, Sydney, Australia.
2018 Institute of Cancer Research, London, UK.
2018 EMBO Symposium on ‘DNA Replication’, Heidelberg, Germany (Symposium speaker and Chair).
2018 14th Copenhagen Bioscience Conference on ‘Protein Signaling’, Favrholm, Denmark (Symposium speaker).
2018 School of Life Sciences, Peking University, Beijing, China
2018 7th icBEST Conference on ‘DNA damage repsonses’ Shenzhen, China (Symposium speaker).
Organization of international conferences:
2002 Keystone Symposium on ‘DNA helicases, Cancer and Aging’ Tahoe City, California, USA (jointly with Dr J. Campisi).
2003 EU Research and Training Network meeting on ‘Genome stability and cell cycle checkpoints’, Oxford, UK.
2007 Keystone Symposium on ‘Genome Instability and Repair’, Breckenridge, Colorado, USA (jointly with Drs. N. Maizels and D. Roth).
2014 Fusion Conference on ‘DNA Replication as a source of DNA damage: from molecules to human health’, Casablanca, Morocco (jointly with Dr Oscar Fernandez-Capetillo).
2016 Benzon Foundation Conference on ‘Genome instability and neurodegeneration’, Copenhagen, Denmark.
2017 Fusion Conference on ‘DNA Replication as a source of DNA damage: from molecules to human health’, Rome, Italy (jointly with Dr Oscar Fernandez-Capetillo).

Publication related metrics (as of June 1st, 2018):
 H-index: 81
 Total number of citations (Web of Science): 19,671
 Average citations per paper: 70
 Most cited paper: Wu and Hickson, Nature (2003) cited 699 times
 64 articles cited more than 100 times, and 28 cited more than 200 times