Karim Labib's Research Group

Labib Lab Website | Pubmed | Biography


Chromosome replication and genome integrity

We study how cells copy their chromosomes, since defects in this process lead to human diseases such as cancer.  All cells must duplicate their chromosomes before cell division, so that the two daughter cells each receive a complete copy of the genetic blueprint, which is contained within the chromosomes in DNA.  Mistakes in this process can be lethal, or else can make cells proliferate out of control and produce a tumour.

Our lab studies a large molecular 'machine' known as the replisome, which is the central player in the process of chromosome duplication.  The assembly and disassembly of the replisome is very tightly controlled, to ensure that cells make just one copy of each chromosome before cell division.

Much of our work is focussed on replisome disassembly.  We discovered many of the mechanisms that control this process and found that cells mark the replisome for disassembly after chromosome duplication is complete, by coupling a small protein known as ubiquitin to one of the core replisome components.  Surprisingly, we found that animal cells also have a second pathway for replisome disassembly, which acts when cells try to divide before the process of chromosome replication has been completed.  Our work involves a wide range of methods, often using insights from studying simple creatures such as yeast or worms, to guide our work with mammalian cells.  Recently we managed to reconstitute the process of replisome disassembly in a test tube, which provides a particularly powerful approach to studying the process in molecular detail.

Some of the factors that are important for replisome disassembly have been shown to be mutated or misregulated in human diseases including cancers.  A deeper understanding of replisome function and disassembly will help us to understand how cells normally keep our bodies healthy, and will also provide new insights into what goes wrong when cancers develop.

Karim's group in the Caledonian forest at Glen Tanar, 60 miles north of Dundee, on a lab retreat on 11th December 2019
Karim's group in the Caledonian forest at Glen Tanar, 60 miles north of Dundee, on a lab retreat on 11th December 2019

People

Johanna Ainsworth | CRUK 4-year PhD Studentship
Thomas Deegan | Postdoctoral Fellow
Cecile Evrin | Postdoctoral Fellow
Ryo Fujisawa | Postdoctoral Fellow
Thanh Le | Postdoctoral Fellow
Cristian Polo Rivera | CRUK 4-year PhD Studentship
Remi Sonneville | Postdoctoral Fellow
Fabrizio Villa | Senior Research Associate
Yisui Xia | Postdoctoral Fellow

Selected Publications

1   Tom D Deegan, Pragya P Mukherjee, Ryo Fujisawa, Cristian Polo Rivera, Karim Labib (2020) CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold Elife 9 e60371
2   Sonneville, R, Bhowmick, R, Hoffmann, S, Mailand, N, Hickson, ID & Labib, K (2019) TRAIP drives replisome disassembly and mitotic DNA repair synthesis at sites of incomplete DNA replication. eLife 8 1-19
3   Deegan, T, Baxter, J, Ortiz Bazan, M, Yeeles, JTP & Labib, K (2019) Pif1-Family Helicases Support Fork Convergence during DNA Replication Termination in Eukaryotes Mol Cell 74 231-244
4   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. 19(5) 468-479
5   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
6   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
7   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