School of Life Sciences

University of Dundee

Professor Karim Labib FRSE

Chromosome replication and genome integrity
Position: 
Professor of Genome Integrity
Affiliation: 
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 384108, int ext 84108
Email: 
Website: 
Group webpages

Research

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.
 

Publications

Top Ten Publications

Sonneville, R., Bhowmick, R. Hoffmann, S., Mailand, N., Hickson, I.D., Labib, K. (2019) TRAIP drives replisome disassembly and mitotic DNA repair synthesis at sites of incomplete DNA replication. eLife, 8:e48686. Doi: 10.7554/eLife.48686.

 

Deegan, T.D., Baxter, J., Ortiz-Bazan, M.A., Yeeles, T.P. and Labib, K.P.M. (2019) Pif1-family helicases support fork convergence during DNA replication termination in eukaryotes. Mol Cell, 18, 231-244.

 

Mukherjee, P.P. and Labib, K.P.M. (2019) In Vitro Reconstitution Defines the Minimal Requirements for Cdc48-dependent Disassembly of the CMG helicase in Budding Yeast.  Cell Rep., 28, 2777-2783

 

Deng L, Wu RA, Sonneville R, Kochenova OV, Labib K, Pellman D, Walter JC. (2019) Mitotic CDK Promotes Replisome Disassembly, Fork Breakage, and Complex DNA Rearrangements. Mol Cell, 73, 915-929

 

Evrin C, Maman JD, Diamante A, Pellegrini L, Labib K. (2018) Histone H2A-H2B binding by Pol α in the eukaryotic replisome contributes to the maintenance of repressive chromatin. EMBO J., 37, pii: e99021. doi: 10.15252/embj.201899021

 

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, 468-479.

 

Maric M, Mukherjee P, Tatham MH, Hay R, Labib K. (2017) Ufd1-Npl4 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 125359"