Meet the team

Figures representing Genomics, Biochemistry, Cryo-EM, AlphaFold, Biophysics, Proteomics
The team employs truly interdisciplinary approaches including biochemistry, cryo-EM, high resolution genomics, chemical biology, genetics and molecular dynamics simulations to obtain holistic understanding of biological processes.
DNA licensing
Human helicase loading, also termed DNA licensing, must be controlled accurately; otherwise, under- or over-replication could occur, resulting in severe genomic instability and promoting tumorigenesis.
Figures representing Genomics, Biochemistry, Cryo-EM, AlphaFold, Biophysics, Proteomics
The Speck lab has reconstituted human helicase loading with purified proteins and studies the regulation of this process.​
Scientific figures relating to MCM2-7 and its structure
We study the genomic footprint and structure of the MCM2-7 helicase, discovering how the enzyme is organised and how it functions.​

DNA replication Research

“How does DNA replication start and how is it controlled?”

DNA replication requires complete control and a high level of fidelity – incorrectly replicating DNA can have disastrous results, ranging from cell death to disease.  

The helicase is an enzyme essential in DNA replication. It “unwinds” the DNA strands so replication can begin. A set of proteins, origin recognition complex 1-6, helps to guide the helicase to its correct starting position. Not much is known about how DNA replication sites are chosen or how access by the helicase is controlled. 

Our research focuses on these replication factors. We want to find out how they function and how they help to organise DNA into tightly packed and loose sections, which in turn regulate gene expression. 

We use a range of interdisciplinary approaches, including biochemistry, high-resolution genomics, genome-wide AlphaFold predictions, and proteomics 

We also use cryogenic electron microscopy, where samples are cooled to very low temperatures to preserve their structures before being studied under the microscope.  

With a better understanding of these replication factors, we hope we can find out more about disease-associated processes and develop novel DNA replication inhibitors that could help treat cancers. 

“We study how DNA replication is controlled, how this process becomes misregulated in disease and use our insights to develop novel DNA replication inhibitors.”

The objective of Speck Lab is to discover new mechanisms in initiation of DNA replication and to understand the function of replication factors in heterochromatin formation and epigenetic memory. This knowledge is used to understand disease-associated processes and in order to develop novel DNA replication inhibitors. The team employs truly interdisciplinary approaches including biochemistry, cryo-EM, high resolution genomics, chemical biology, genetics and molecular dynamics simulations to obtain holistic understanding of biological processes.

To find out more visit Specklab.com and the group leader’s Imperial College website.

Diagram
a–d Three different structural states (I-III) derived from the same MD-(ATPγS) cryo-EM data set. a Cryo-EM 3D auto-refined map (see Methods) of MD-(ATPγS) state I. b Composite map (see Methods) of MD-(ATPγS) state II. c, d Composite map (see Methods) of MD-(ATPγS) state III with side and top views. DH at 3.2 Å mean resolution and DDK at 3.6 Å mean resolution. The map density corresponding to each protein subunit component of the complex is coloured according to the key shown.

Our research is supported by

BBSRC
Cancer research uk logo

Selected publications

Reuter LM, Khadayate SP, Mossler A, Liebl K, Faull SV, Karimi MM, Speck C. (2024). MCM2-7 loading-dependent ORC release ensures genome-wide origin licensing. Nat Commun. 2024 Aug 24;15(1):7306. doi: 10.1038/s41467-024-51538-9

Saleh A., Noguchi Y., Aramayo R., Ivanova ME., Stevens KM., Montoya A., Sunidhi S., Carranza NL., Skwark MJ., Speck C. (2022). The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamerNat Commun 13, 2915. https://doi.org/10.1038/s41467-022-30576-1

Feng X., Noguchi Y., Barbon M., Stillman B., Speck C., Li H. (2021). The structure of ORC-Cdc6 on an origin DNA reveals the mechanism of ORC activation by the replication initiator Cdc6Nat Commun 12, 3883. https://doi.org/10.1038/s41467-021-24199-1

Yuan Z., Schneider S., Dodd T., Riera A., Bai L., Yan C., Magdalou I., Ivanov I., Stillman B., Li H., and Speck C. (2020). Structural mechanism of helicase loading onto replication origin DNA by ORC-Cdc6Proc Natl Acad Sci U S A117(30):17747-17756. doi: 10.1073/pnas.2006231117

Noguchi Y., Yuan Z., Bai L., Schneider S., Zhao G., Stillman B., Speck C., Li H. (2017). The cryo-EM structure of Mcm2-7 on DNA suggests a new lagging-strand DNA extrusion modelProc Natl Acad Sci U S A114(45):E9529-E9538. doi:10.1073/pnas.1712537114

Yuan Z., Riera A., Bai L., Sun J., Nandi S., Spanos C., Chen ZA., Barbon M., Rappsilber J., Stillman B., Speck C. and Li H. (2017). Structural basis of MCM2-7 replicative helicase loading by ORC-Cdc6 and Cdt1Nat Struct Mol Biol., 24, 316–324. https://doi.org/10.1038/nsmb.3372