Karim Labib's Research Group

Labib Lab Website | Pubmed | Biography


Chromosome replication and genome integrity

How can the inherent defects in chromosome replication that characterise many cancer cells be exploited therapeutically?  One of the most important and complex challenges for any cell is to copy the genome before cell division.  The scale of the challenge is enormous, and eukaryotic chromosome replication is particularly complex and fascinating, since it involves many other processes in addition to DNA synthesis, such as chromatin regeneration, the establishment of cohesion between the newly formed sister chromatids, and a myriad of DNA repair processes.

Our lab studies the large multi-protein machine known as the replisome, which is the central player in the process of chromosome duplication at DNA replication forks.  The assembly and disassembly of the replisome are regulated extensively by post-translational modifications, ensuring that the replisome makes just one copy of each chromosome per cell cycle.  

We recently discovered that replisome disassembly requires the Cdc48 ‘segregase' and is regulated by a ubiquitylation pathway at the end of chromosome replication.  We found that yeast and metazoa use different E3 ligases to ubiquitylate the DNA helicase that forms the core of the replisome.  Moreover, metazoa have a second pathway for replisome disassembly that acts during mitosis, requiring a factor that is mutated in various human cancers.  This suggests that a deeper understanding of replisome disassembly is likely to identify interesting new targets for future therapies.

Labib Lab Group Photo

People

Thomas Deegan | Postdoctoral Researcher
Cecile Evrin | Postdoctoral Fellow
Ryo Fujisawa | Associate Staff
Ye Hong | Postdoctoral Researcher
Ross Madden | PhD Rotation Student
Pragya Mukherjee | PhD Student
Maria Ortiz Bazan | Postdoctoral Researcher
Remi Sonneville | Postdoctoral Researcher
Fabrizio Villa | Senior Research Associate
Yisui Xia | Postdoctoral Researcher

Selected Publications

Sonneville R, Moreno SP, Knebel A, Johnson C, Hastie CJ, Gartner A, Gambus A, Labib K. (2017) CUL-2LRR-1 and UBXN-3 drive replisome disassembly during DNA replication termination and mitosis Nat Cell Biol. Apr 3. 1038/ncb3500.
Maric M, Mukherjee P, Tatham MH, Hay R, Labib K. (2017) Recruit Cdc48 for Disassembly of Ubiquitylated CMG Helicase at the End of Chromosome Replication. Cell Rep. 18 3033-3042.
Villa, F. Simon, A. C. Ortiz Bazan, M. A. Kilkenny, M. L. Wirthensohn, D. Wightman, M. Matak-Vinkovic, D. Pellegrini, L. Labib, K. (2016) Ctf4 Is a Hub in the Eukaryotic Replisome that Links Multiple CIP-Box Proteins to the CMG Helicase Mol Cell 63 385-396
Maculins, T., Nkosi, P. J., Nishikawa, H., Labib, K. (2015) Tethering of SCF(Dia2) to the Replisome Promotes Efficient Ubiquitylation and Disassembly of the CMG Helicase Curr Biol 25 2254-9
Maric, M., Maculins, T., De Piccoli, G., Labib, K. (2014) Cdc48 and a ubiquitin ligase drive disassembly of the CMG helicase at the end of DNA replication Science 346 1253596
Sengupta, S., van Deursen, F., de Piccoli, G., Labib, K. (2013) Dpb2 integrates the leading-strand DNA polymerase into the eukaryotic replisome Curr Biol 23 543-552