“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 hetero-chromatin formation and epigenetic memory. This knowledge is used to understand disease associated process 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.
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
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 hexamer. Nat 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 Cdc6. Nat 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-Cdc6. Proc Natl Acad Sci U S A. 117(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 model. Proc Natl Acad Sci U S A. 114(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 Cdt1. Nat Struct Mol Biol., 24, 316–324. https://doi.org/10.1038/nsmb.3372