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.
* Postdoctoral Position for 2017 *
Research Associate in Biochemistry
This is an ideal opportunity for an enthusiastic and highly creative scientist to join a dynamic research team with excellent collaborators and facilities. The successful applicant will use cutting-edge biochemical approaches to investigate fundamental biological mechanisms in eukaryotic DNA replication with therapeutic potential.
The project will address how key DNA replication factors function and how they are regulated, which is crucial to understand how cancer development is initiated and will serve as a stepping-stone for the development of novel replication inhibitors with potential as chemotherapeutic drugs. The successful candidate will take advantage of efficient and well-established reconstituted systems and in vivo approaches (Evrin et al PNAS 2009, Fernandez-Cid et al Mol Cell 2013, Sun et al NSMB 2013, Samel et al G&D 2014, Sun et al G&D 2014 and Chang et al 2015 Elife) to address how the replicative helicase becomes loaded onto DNA. A recent high resolution structure of the replicative helicase in complex with its loader (Yuan et al NSMB 2017) has provided key insights into this process. This project will take advantage of this knowledge to reveal the fundamental mechanism of helicase loading. The research will involve design of constructs, expression and purification of proteins & protein complexes using bacteria and yeast. The purified factors will be used for the development of novel biochemical assays, structural analysis in collaboration with other group members and analysis of protein dynamics by FRET assays. The applicant will be working as part of a team, and will have ample opportunity to drive the project’s direction in a creative way.
The successful candidate will enjoy intensive interactions with group members specialised in cryo-EM, biochemistry or in vivo approaches generating a collaborative and highly productive atmosphere, with substantial opportunities for advanced training. The lab is very well equipped for biochemistry and structural EM work and has direct access to a local cryo-EM facility and the Titan Krios as founding member of the LonCEN consortium.
By joining the group, the candidate will not only participate in high profile research projects, but will be also directly mentored by Professor Speck in grant writing, networking and publishing. This will prepare the post holder ideally for the next career move.
The candidate should have a PhD in Biochemistry or neighbouring disciplines, a strong publication record and extensive expertise in protein biochemistry. A background in the areas of molecular machines, chromatin biology, yeast genetics, structure determination & modelling, DNA replication, cell cycle, DNA repair, and the broader area of genome stability would be of advantage, but is not necessary.
The latest expected start date is autumn 2017.
This is a full-time, three year position (HM2017034) with a salary range of : £36,070 to £40,030 per annum.
Informal enquiries may be made to Prof. Christian Speck (firstname.lastname@example.org).
For more details please see: http://www.specklab.com/vacancies/.
Apply online via our website at: http://www3.imperial.ac.uk/employment (select “Job Search” then enter the job title or vacancy reference number into “Keywords”). Please complete and upload an application form as directed quoting the appropriate reference number (HM2017034).
Closing Date: 4 April 2017 (Midnight)
* PhD studentship for 2017 *
Investigating key mechanisms in DNA replication and cancer.
Supervisor 1: Professor Speck (DNA Replication Group)
Supervisor 2: Professor Gil (Cell Proliferation Group)
The purposes of this PhD is to generate an advanced light-regulated system (Kawano et al Nature Commun 2015), which allows us to have full control over the DNA insertion/extrusion process. After establishing this in the lab, the successful student will use this technique to investigate how the replication fork is used to guarantee genome stability. The DNA replication group employs Saccharomyces cerevisiae, which is the most used model organism to study DNA replication, as replication factors are well conserved between yeast and humans. The design of the photo-switch will employ de novo structure prediction and structure guided protein engineering techniques and is supported by the recent cryo-electron microscopy insights of the group (Yuan et al Nature Struc Mol Biol 2017). Importantly, the student will address in the Gil laboratory, whether the developed system can be applied in the human context and whether closing the gate specifically harms cancer cells (Woodward et al J Cell Biol 2006). Altogether, this high-profile project will offer the candidate significant training opportunities, a stimulating research environment and deep insights into DNA replication, genome stability and cancer.
For more details please see: http://www.specklab.com/vacancies/
We seek for a talented and highly-motivated graduate student with particular good knowledge of biochemical and/or molecular biology methods. Interests in project development, good communication skills and proficiency in English are requirements for this project. Ideally, the candidate has working experience with yeast genetics, synthetic biology, cell culture or protein modelling.
Applicants should have:
- Settled status in the UK, meaning they have no restrictions on how long they can stay
- Been ‘ordinarily resident’ in the UK for three years prior to the start of the studentship. This means they must have been normally residing in the UK (apart from temporary or occasional absences)
- Not been residing in the UK wholly or mainly for the purpose of full-time education. (This does not apply to UK or EU nationals).
Starting date: Between 1st of June and 1st of October
Informal enquiries may be made to Prof. Christian Speck (email@example.com).
Closing Date: 23 April 2017.
Major scientific accomplishments
- Elucidation of the structural basis of MCM2-7 replicative helicase loading by ORC-Cdc6 and Cdt1 (Natural Structural & Molecular Biology, 2017)
- 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 ...
Max for being awarded a prestigious two year Deutsche Forschungsgemeinschaft (DFG) Research Fellowship.
Indiana for receiving the CSC Local Hero Award.
Katalin Kondas join the lab as a Postdoctoral Daphne Jackson Fellow. Big welcome!
Group retreat in Norfolk at the Grange Manor House - lots of fun.
Henry for passing his MSc viva with distinction.
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.
Alberto new toy, a graphics processing unit (GPU)-accelerated workstation, has arrived.
Katalin Kondas, who will join the Group in September, was awarded a two year Daphne Jackson Trust Fellowship.
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.
Marta and Indiana participated in the CSC microscopy workshop for local primary school children from Ark Conway Academy and Old Oak Primary School.
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 (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).
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 Professor of Genome Biochemistry & Molecular Biology at the Institute for Clinical Sciences in the Faculty of Medicine. He is a Fellow of the Royal Society of Biology (FRSB) and has been the recipient of two prestigious research fellowships from an US charity foundation and the Max Planck Society, research grants from the UK research councils, and received the Wellcome Trust Investigator award in 2015. Christian served as an invited panel member during the scientific evaluation of the Horizon 2020-MSCA-IF-2016- LIF and the French National Research Agency - ANR. 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 as a session Chair to the Cold Spring Harbor Replication meeting and the FEBS Congress . 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 Imperial College, 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., 2017, Structural basis of Mcm2-7 replicative helicase loading by ORC-Cdc6 and Cdt1., Nat Struct Mol Biol, Vol:24, Pages:316-324
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