Professor Karim Labib

Chromosome duplication and genome integrity

All life on Earth depends on cells copying their chromosomes with exquisite fidelity, to preserve the integrity of the genetic blueprint that is encoded in DNA.  Chromosome duplication is especially challenging in species with large genomes such as humans, where each cell has to copy around six billion base pairs of DNA, before the sister chromatids are segregated to opposite poles of the cell during mitosis.  We study how cells achieve this amazing feat, by regulating the assembly and disassembly of the replication machinery, protecting the replication machinery at sites of DNA damage, and rapidly processing sites of incomplete replication during mitosis to facilitate successful chromosome segregation.

Although the replication machinery has been very highly conserved during eukaryotic evolution, important differences of regulation have also emerged, and our lab focusses on mechanisms that are specific to animal cells.  We take a multi-disciplinary approach to studying such mechanisms, ranging from reconstituted biochemistry and structural approaches, to in vivo approaches in the early embryo of the nematode Caenorhabditis elegans, combined with studies in mammalian cells.  The remarkable efficiency of genome maintenance breaks down in human cancer and tumour cells are often riddled with mutations and structural rearrangements of their chromosomal DNA.  A deeper understanding of the intimate links between chromosome duplication and genome integrity is likely to inspire new approaches to cancer treatment in the future.

Selected Publications

• Fujisawa, R. and Labib, K.P.M. (2024) TTF2 drives mitotic replisome disassembly and MiDAS by coupling the TRAIP ubiquitin ligase to Polε. bioRxiv, https://doi.org/10.1101/2024.12.01.626218.
• Villa, F., Ainsworth, J. and Labib, K.P.M. (2024) USP37 protects mammalian cells during DNA replication stress by counteracting CUL2-LRR1 and TRAIP. bioRxiv, https://doi.org/10.1101/2024.09.03.610971.
• Polo Rivera, C., Deegan, T. and Labib, K.P.M. (2024) CMG helicase disassembly is essential and driven by two pathways in budding yeast.  The EMBO Journal, 43(18):3818-3845. doi: 10.1038/s44318-024-00161-x.
• Evrin C., Alvarez V., Ainsworth J., Fujisawa R., Alabert C. and Labib K.P.M. (2023) DONSON is required for CMG helicase assembly in the mammalian cell cycle.  EMBO Rep. e57677. doi: 10.15252/embr.202357677.
• Xia, Y., Sonneville, R., Jenkyn-Bedford, M., Ji, L., Alabert, C., Hong, Y., Yeeles, J.T.P. and Labib, K.P.M. (2023) DNSN-1 recruits GINS for CMG helicase assembly during DNA replication initiation in C. elegans. Science, doi:10.1126/science.adi4932.
• Jenkyn-Bedford M, Jones ML, Baris Y, Labib KPM, Cannone G, Yeeles JTP, Deegan TD (2021) A Conserved Mechanism for Regulating Replisome Disassembly in Eukaryotes Nature 600 743-747 doi:10.1038/s41586-021-04145-3 PMID: 34700328
• Xia Y, Fujisawa R, Deegan TD, Sonneville R, Labib KPM (2021) TIMELESS-TIPIN and UBXN-3 promote replisome disassembly during DNA replication termination in Caenorhabditis elegans The EMBO Journal  e108053 doi:10.15252/embj.2021108053 PMID: 34269473
• Villa F, Fujisawa R, Ainsworth J, Nishimura K, Lie-A-Ling M, Lacaud G, Labib KP. (2021) TRAIP and p97 control CMG helicase disassembly in the mammalian cell cycle EMBO Rep  e52164 doi:10.15252/embr.202052164 PMID: 33590678
• Le TT, Ainsworth J, Polo Rivera C, Macartney T, Labib K (2021) Reconstitution of human CMG helicase ubiquitylation by CUL2LRR1 and multiple E2 enzymes Biochem J  BCJ20210315 doi:10.1042/BCJ20210315 PMID: 34195792
• 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 PMID: 32804080
• 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 PMID: 30850330
• 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 PMID: 31545170
• 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 PMID: 30849395

Contributes lectures / tutorials to:

• Advanced Gene Regulation and Expression– year 4

and also provides supervision for:

• Honours student projects
• Rotation projects for Masters students
• PhD projects for graduate students

Environmentally Sustainable Research

Karim Labib is Head of Sustainability and Climate Action for the School of Life Sciences and chairs the EMBO Lab Sustainability Award Advisory Board.