SPECK LAB OVERVIEW
The objective of our group is to discover new mechanisms in the initiation and elongation of DNA replication and to understand the function of replication factors in hetero-chromatin formation. We have recently reconstituted the loading of the eukaryotic replicative helicase onto DNA, an essential step in DNA replication and use this system to address the mechanism and regulation of two key events: the loading of the eukaryotic DNA helicase onto DNA and the kinase dependent activation of the helicase. More recently, we have also started to investigate the role of the helicase loading factors in epigenetic memory, which has important implications for human disease and aging.
Major scientific accomplishments
- Elucidation of the MCM2-7 double-hexamer structure reveals key mechanism in helicase loading and activation (Genes & Development, 2014a)
- Identification of the DNA entry gate of the MCM2-7 helicase during helicase loading (Genes & Development, 2014b)
- Characterisation of the first structure of an eukaryotic replicative helicase in complex with its loading factors (Nature Structural & Molecular Biology, 2013)
- Identification of a novel ATPase dependent pre-RC intermediate that is surveyed by a quality control mechanism for genomic stability (Molecular Cell, 2013)
- Discovery of a pre-RC intermediate that forms in the absence of ATP-hydrolysis and contains one copy of all 18 pre-RC factors (Nucleic Acids Research, 2013)
- Reconstitution of pre-RC formation and discovery of the MCM2-7 double-hexamer as a central DNA replication intermediate (Proceedings of the National Academcy of Science of the United States of America, 2009)
- Identification of an ATPase-dependent mechanism that allows sequence specific recognition of the DNA replication origin (Journal of Biological Chemistry, 2007)
- Elucidation of the ORC-Cdc6 complex structure and its sequence specific origin binding activity (Nature Structural & Molecular Biology, 2005)
- Identification of key mechanism in initiation of DNA replication in bacteria (The EMBO Journal, 2001)
- Discovery of an ATP dependent mechanism to coordinate initiation of DNA replication with transcriptional regulation in bacteria (The EMBO Journal, 1999)
Funding (past and present)
The Group is or has been funded by the BBSRC, DFG, EPSRC, EU (ERASMUS, Marie Curie), Wellcome Trust, Leukemia & Lymphoma Society, Max Planck Society, and MRC.
Group News & Congratulations to ...
Christian has won the Wellcome Trust Investigator Award.
The DNA replication group has been awarded a project grant by the BBSRC to investigate mechanism in helicase loading.
Alberto and Cecile for publishing "Cdc6 ATPase activity disengages Cdc6 from the pre-replicative complex to promote DNA replication" in eLife (in the Press). Conratulations to Alberto & Cecile for succeeding with this large project.
Christian has been promoted to Reader in Genome Biochemistry & Molecular Biology
Alice presented succesfully her Master project at the Beuth Hochschule fur Technik, Berlin and obtained the highest marks for the presentation and written report.
Christian for being selected as editorial board member of the Biochemical Journal.
Noelia and Marta participated in the CSC microscopy workshop for a local primary school - well done!
Alberto for publishing the review "MCM2-7 - Opening the gate to DNA Replication" in the journal Cell Cycle.
Christian for becoming elected Fellow of the Royal Society of Biology
* NEW PHD POSITIONS AVAILABLE FOR 2015/2016 *
Imperial College PhD Scholarship Scheme I am considering now to sponsor an excellent UK, European or International candidate for the fully funded Imperial College PhD Scholarship Scheme - academic year 2015/2016. Please contact me directly to discuss potential research proposals (firstname.lastname@example.org). 3.5 YEAR MRC DTP Studentships Candidates with an interest in genomic stability, epigenetics and disease please contact Christian to discuss potential research proposals. Competitive candidates for each of these projects will hold a degree in biochemistry or closely related subject with an outstanding academic record and some practical research experience. Applications can be submitted online through the Imperial College website; informal enquiries (CV/covering letter) may be sent to Christian via email (email@example.com).
POTENTIAL PhD PROJECTS
Analysis of the human replicative helicase for normal function and disease - a cross-disciplinary approach More than one in three people in the UK will be diagnosed with some form of cancer during their lifetime. Cancer can arise for many reasons, but a large source of mutations originates from mistakes during the complex DNA replication process. The regulated loading of the replicative helicase onto replication origins is a prerequisite for the establishment of functional replication forks, but misregulation of this process results in genomic instability and promotes tumorigenesis. We have studied the process of helicase loading using budding yeast as a model organism. A reconstituted system using purified proteins was developed and consequently used to study how the helicase becomes assembled at replication origins. We identified several crucial regulatory mechanisms of helicase loading and described the first cryo-EM structure of the eukaryotic helicase in complex with its loader (Evrin et al PNAS, Fernandez-Cid et al Mol Cell and Sun et al Nature Structural & Molecular Biology…). The new PhD project will investigate now human helicase loading. The main aims of the project are to discover novel regulatory mechanism of helicase loading, which are medically relevant and don’t exist in yeast. The project will feature protein expression, purification and enzymatic assays, synthetic-engineering and chemical-biology approaches, coupled with electron microscopy and single-molecule methods in collaboration with David Rueda, ICL. These cross-disciplinary approach has the potential to identify crucial mechanisms of DNA replication, which are misregulated in cancer and other diseases. Thus, the proposed work will form the basis for the development of helicase loading inhibitors with potential in anti-cancer therapy.
Other positions available
Bachelor/ MRes/ Master Students (UK/EU/International)
Any students interested in pursuing research in our group should contact Christian Speck by email (firstname.lastname@example.org) for potential openings. Please send your CV and explain your interest in the specific research area. European/International students must obtain independent funding through ERASMUS+ or via a government bursary to cover their expenses.
Any students interested in pursuing postgraduate research in our group should contact me directly by email (email@example.com); all prospective applicants should have or expect to obtain a 1st class honours degree (or equivalent) in biochemistry, or a closely related discipline.
If you are interested in joining the lab as a postdoc please contact Christian Speck by email (firstname.lastname@example.org) sending your CV and explaining your interest in this specific research area. Outstanding PhD students are encouraged to make contact as early as possible to discuss potential fellowship applications, for example from the European Union, HFSP, etc.. Full assistance will be given in preparing a competitive research proposal with bridging funding being available to the candidates; we have an exceptional track record in accelerating the careers of outstanding postdoctoral researchers, with fellowships from Marie Curie, DFG and MRC awarded to members of our lab.
The SPECK LAB
About Dr. Christian Speck
Christian is a Reader in Genome Biochemistry & Molecular Biology (Associate Professor) at the Institute for Clinical Sciences in the Faculty of Medicine. He has been the recipient of two prestigious research fellowships from an US charity foundation and the Max Planck Society and recently he has been elected Fellow of the Royal Society of Biology. He sits on the editorial board of the Journals Microbial Cell , Advances in Molecular Biology, Biochemical Journal, chairs the Institutes Athena Swan committee and sits on the Clinical Science Centre Postgraduate Education Committee. He has given oral presentations at the renowned Cold Spring Harbor DNA replication meeting for the last 10 years. Christian has been invited to numerous European and UK universities for research seminars and most recently to the Cold Spring Harbor Replication meeting and the 41st FEBS Congress as a session Chair. During his B.Sc. degree in biotechnology at the Beuth Hochschule of Berlin, Dr. Speck undertook a project at Genentech Inc in South San Francisco USA for 6 month in the laboratory of Dave Goeddel (CSO, Genentech) to get industry experience. Christian obtained his Ph.D. in biochemistry from the Free University of Berlin under the guidance of the late Prof. Walter Messer working at the Max-Planck institute of Molecular Genetics, while being funded by a Max-Planck Fellowship to study bacterial DNA replication. This work resulted in 3 first author publications including two in EMBO Journal. He then moved to the US to work with Bruce Stillman, President of the Cold Spring Harbor Laboratory, while being supported by a Leukaemia and Lymphoma Research Fellowship exploring eukaryotic DNA replication and the role of Cdc6 in initiation of DNA replication. This work resulted in 4 first author publications in Nature Structural & Molecular Biology, PNAS and JBC. Following this period of training he moved to Imperial College London to establish his group in 2006 at MRC-CSC and since 2013 at the Institute of Clinical Science first as a lecturer and since 2015 as a Reader. His group reconstituted the loading of the replicative helicase with purified proteins (F1000 – excellent) and identified a series of crucial mechanisms and regulatory principles in DNA replication being published in prominent journals such as Molecular Cell, Nature Structural & Molecular Biology Genes & Development and PNAS.
et al., 2015, Cdc6 ATPase activity disengages Cdc6 from the pre-replicative complex to promote DNA replication., Elife, Vol:4
et al., 2015, A reconstituted system reveals how activating and inhibitory interactions control DDK dependent assembly of the eukaryotic replicative helicase, Nucleic Acids Research, Vol:43, ISSN:0305-1048, Pages:10238-10250
et al., 2014, Structural and mechanistic insights into Mcm2-7 double-hexamer assembly and function, Genes & Development, Vol:28, ISSN:0890-9369, Pages:2291-2303
et al., 2014, A unique DNA entry gate serves for regulated loading of the eukaryotic replicative helicase MCM2-7 onto DNA, Genes & Development, Vol:28, ISSN:0890-9369, Pages:1653-1666
Riera A, Tognetti S, Speck C, 2014, Helicase loading: How to build a MCM2-7 double-hexamer, Seminars in Cell & Developmental Biology, Vol:30, ISSN:1084-9521, Pages:104-109
et al., 2013, Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA, Nature Structural & Molecular Biology, Vol:20, ISSN:1545-9993, Pages:944-+
et al., 2013, An ORC/Cdc6/MCM2-7 Complex Is Formed in a Multistep Reaction to Serve as a Platform for MCM Double-Hexamer Assembly, Molecular Cell, Vol:50, ISSN:1097-2765, Pages:577-588
et al., 2009, A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication, Proceedings of the National Academy of Sciences of the United States of America, Vol:106, ISSN:0027-8424, Pages:20240-20245
et al., 2005, ATPase-dependent cooperative binding of ORC and Cdc6 to origin DNA., Nature Structural & Molecular Biology, Vol:12, ISSN:1545-9993, Pages:965-971