SPECK LAB OVERVIEW
The objective of the group is to discover new mechanisms in initiation of DNA replication and to understand the function of replication factors in hetero-chromatin formation and epigenetic memory. This knowledge is used to understand disease associated process and in order to develop novel DNA replication inhibitors. We employ truly interdisciplinary approaches including biochemistry, cryo-EM, high resolution genomics, chemical biology, genetics and molecular dynamics simulations to obtain holistic understanding of biological processes.
We collaborate with ICL Chemistry (Anna Barnard, ICL White City Campus) and MRC-LMS (Alexis Barr, Hammersmith Campus) to exploit our biological insights for inhibitor development. Together with DeepChain we use molecular dynamics simulations and AI driven analysis of protein sequences to understand the function of multi-protein complexes.
Enquires from motivated and exceptional students and postdocs to work in the group are always welcome. Please send full CV and cover letter to: firstname.lastname@example.org
Major scientific accomplishmenTs
- The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer (Nature Communications 2022)
- The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6 (Nature Communications 2021)
- Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6 (Proceedings of the National Academy of Science of the United States of America, 2020)
- The cryo-EM structure of Mcm2-7 on DNA suggests a new lagging-strand DNA extrusion model (Proceedings of the National Academy of Science of the United States of America, 2017)
- Structural basis of MCM2-7 replicative helicase loading by ORC-Cdc6 and Cdt1 (Nature Structure & 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, CRUK, DFG, JSPS, EPSRC, EU (ERASMUS, Marie Curie), Imperial College, Wellcome Trust, Leukemia & Lymphoma Society, Max Planck Society, and MRC.
Group News & Congratulations to …
Goodbye Audrey. We will miss you and wish you all the best for the future. You are an absolute star!!!
Shivni Chauhan joins the lab as a MRes student and Darsh Vithlani joins the lab as a summer student. Big welcome!
Big congratulations to Almutasem Saleh for winning a grant from the NVIDIA Academic Hardware Program. Data processing will be quicker now :-)
Jennifer Wells joins the lab as a Postdoc. Big welcome!
Chris Weekes defended his PhD thesis. Many congratulations and enjoy your new job - exciting times!
Lucy Edwardes joins the lab as a PhD student. Big welcome!
Matt Peach joins the lab as a PhD student. Big welcome!
I have visited the construction site of our New Building. In August 2022 we will move in and will enjoy the outstanding views from the 7th floor cafe. The lab is already taking shape. Cool drone footage from construction site is shown below.
Great news - our SAMURII studentship application was successful. In the near future the PhD student will be developing in collaboration with the Rueda, Fuchter and Di Antonio groups a screen for novel DNA licensing inhibitors.
The Speck Lab has been granted a CRUK Discovery Programme Award. Huge congratulations to Vera for generating outstanding preliminary data. This 5-year grant will allow us uncover fundamental mechanisms of human DNA licensing control and its misregulation in cancer.
Nick Chiang joins the lab as a summer student. Big welcome!
Our manuscript titled "The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6" has been accepted in Nature Communications! Huge congratulations to Yasunori and Marta.
The Institute got a brand new Talos 200i microscope and said goodbye to the CM200. Great and very exciting upgrade!
Great News, our iCASE studentship application was successful. We will collaborative with Refeyn Ltd and Professor Rueda to investigate DNA replication by mass photometry and to develop new analysis approaches.
Joshua Tomkins joins the lab as a PhD student. Big welcome!
Lepakshi Ranjha and Marina Ivanova join the lab as Postdocs. Big welcome!
We say good bye to the fantastic Sarah Schneider, who will embark on her new career as the cryo-EM facility manager at EMBL Grenoble. We will miss you wish you all the best for the future.
Work in the lab is slowly starting again...
With Covid-19, lab meetings, journal clubs and 1:1 meetings move to an online platform.
Recruitment during Covid-19. Two fantastic postdocs will be joining in October - could not have hoped for a better outcome.
We had in February our group's third retreat at the beautiful Bellropes country estate. Exploration of scientific concepts, games and model building, lots of cooking and a visit of a brewery.
Great news, our BBSRC grant application was successful! Huge congratulations to Sarah S, Al and Yasunori for writing a fantastic proposal and achieving a superb ranking: 4th out of 89.
Our first data collection on the new LonCEM Titan Krios microscope using the K3 in super-resolution mode has just started. A dream come true...
Jessica Ellins and Shenaz Allyjaun join the lab as PhD students. Big welcome!
Joseph Dobbs joins the Group as a BSc student. Big welcome!
Greta Baltusyte joins the Group as a BA student. Big welcome!
Halil Bounoua joins the lab to carry out his BSc research project. Big welcome!
Sarah Faull joins the lab as a Postdoc. Big welcome!
Jillian Tay joins the lab to carry out her MRes research project. Big welcome!
Our eight GPU Cluster is almost ready for action - can't wait to see it happen...
Megan Turner joins the lab to carry out her MSc research project. Big welcome!
Audrey Mossler joins the group to gain experience in a UK lab. Big welcome!
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 via a government/charity bursary to cover their expenses.
New fully funded PhD studentships (Imperial College PhD Presidents Scholarship and the MRC DTP studentship) will be advertised when they become available. Candidates that want to apply for scholarships can continue to contact Christian Speck 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. Please indicate in your email for which fellowship you are eligible to apply.
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, JSPS and MRC awarded to members of our lab.
The SPECK LAB
About Prof. 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-2016/2017- LIF, DAAD and the French National Research Agency - ANR. He sits on the editorial board of the Biochemical Journal, chairs the Institutes Athena Swan committee and sits on the Clinical Science Centre Postgraduate Education Committee. 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, Prof. 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 London to establish his group in 2006 at MRC-CSC and since 2013 at Imperial College London, 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. In 2017 he became one of the founding members of the Wellcome Trust funded LonCEM consortium, which was awarded a Titan Krios cryo-EM with K3 detector. In the same year, he became a member of the Imperial College London Centre for Structural Biology (CSB) and in 2018 member of the associated Block Allocation Group (BAG) for flexible access to the Krios 1-4 of eBIC (Diamond Light Source - Harwell). In 2017 Christian, while being supported by Sarah S, has set-up the local cryo-EM screening facility at the Institute of Clinical Sciences. The facility is by now is fully operational and supports the electron microscopy efforts of the whole institute.
et al., 2019, An integrated workflow for crosslinking mass spectrometry., Mol Syst Biol, Vol:15
et al., 2017, Cryo-EM structure of Mcm2-7 double-hexamer on DNA suggests a lagging strand DNA extrusion model, Proceedings of the National Academy of Sciences of the United States of America, Vol:114, ISSN:0027-8424, Pages:E9529-E9538
et al., 2017, From structure to mechanism – understanding initiation of DNA replication, Genes & Development, Vol:31, ISSN:1549-5477, Pages:1073-1088
et al., 2017, Structural basis of MCM2-7 replicative helicase loading by ORC-Cdc6 and Cdt1, Nature Structural & Molecular Biology, Vol:24, ISSN:1545-9993, Pages:316-324
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:1362-4962, Pages:10238-10250
Speck C, 2015, Cdc6 ATPase activity disengages Cdc6 from the pre-replicative complex to promote DNA replication, Elife, Vol:4, ISSN:2050-084X
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 Structure Molecular Biology
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