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.
*NEW Postdoctoral Position for 2017*
We are seeking an outstanding Biochemist / Molecular biologist to join our group to work on a Wellcome Trust funded project, for a period of 3 years. The project focuses on understanding the role of human DNA replication factors in origin recognition, assembly of the replication fork and regulated heterochromatin formation. This work offers a great opportunity to discover how human replication factors function and how they are regulated, which is crucial to understand how cancer development is initiated and in order to develop novel replication inhibitors with potential as chemotherapeutic drugs. The research will involve design of constructs, expression and purification of proteins & protein complexes using bacteria and insect cells (multi-bac). The purified factors will be used for the development of novel biochemical assays, structure determination by cryo-electron microscopy, analysis of protein dynamics by FRET assays and inhibitor development. The applicant will be working as part of a team, but will also have ample opportunity to drive the project’s direction in a creative way. Candidates should hold a PhD in the biochemistry/molecular biology area, and preferably have experience in working with proteins.
This position will be advertised in due course, and will start in early 2017; in the meantime, informal enquiries may be made to Prof. Christian Speck (please send your CV via email).
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 ...
Marta for being awarded a bursary from the Biochemical Society UK for the 80th Harden Conference: Machines on Genes IV - Mechanisms of Actions of Large Macromolecular Machines on Genes Across Biological Scales on 31 July - 5 August 2016 at Shrigley Hall Hotel, Macclesfield, UK.
Alberto, who successfully applied for the Cryo-Electron Microscopy and 3D Image Processing course at EMBL
Christian has been promoted to Professor of Genome Biochemistry & Molecular Biology.
Max Reuter joins the lab as a Postdoc. Big welcome!
Sarah new toy arrived - the FEI Vitrobot Mark IV.
Sarah Schneider and Yasanori Noguchi join the lab as Postdocs. Big welcome!
Silvia Tognetti, as the News & Views she wrote got published in Nature Cell Biology.
Christian gave an update of Athena SWAN progress of the institute and presented the mentoring awards at the annual retreat.
Indiana Magdalou joins the group as a lab manager. Big welcome!
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 2016/2017 *
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 2016/2017. Please contact me directly to discuss potential research proposals (email@example.com). 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 (firstname.lastname@example.org).
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 (email@example.com) 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 (firstname.lastname@example.org); 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 (email@example.com) 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 Professor of Genome Biochemistry & Molecular Biology 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, 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. 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