Professor Karim Labib

FRSE

Professor

MRC PPU, School of Life Sciences

Head of Sustainability and Climate Action, School of Life Sciences

Karim Labib
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Biography

Karim studied Natural Sciences at the University of Cambridge, before moving to Oxford as a PhD student with Sir Paul Nurse (Nobel prize for medicine, 2001). Subsequently, Karim spent periods as a postdoctoral fellow with Sergio Moreno in Salamanca, Stephen Kearsey in Oxford and John Diffley in London. In 2001, Karim received a Senior Cancer Research Fellowship to start his group at the Cancer Research UK Manchester Institute. Karim was selected to join the EMBO Young Investigator Programme in 2004, and in 2006 was promoted to a tenured position as a senior group leader at the CRUK Manchester Institute. In 2010, Karim was elected a member of EMBO and received the Hooke medal from the British Society for Cell Biology.

Karim took up his current position as Professor of Genome Integrity at the University of Dundee in 2013, and his group relocated to the MRC PPU. In 2016, Karim was elected a fellow of the Royal Society of Edinburgh, Scotland's national academy.

Karim previously led the selection committee for the EMBO Young Investigator Programme and currently chairs the EMBO Installation Grant Committee. Karim is also a committed environmentalist and leads the MRC PPU’s efforts to reduce the environmental impact of our research. In addition, Karim serves as ‘Head of Sustainability and Climate Action’ for the School of Life Sciences.

Research

Chromosome replication and genome integrity

We study how cells copy their chromosomes before cell division, to ensure that both daughter cells receive a complete copy of the genetic blueprint, which is contained within the chromosomes in DNA. The process of chromosome duplication starts to go wrong in the early development of many human cancers, providing an opportunity to develop new treatments that seek to kill cancer cells without hurting the rest of the body.

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 by phosphorylation and ubiquitylation, to ensure that cells make just one copy of each chromosome before cell division.

Over the last 10 years, much of our work has focussed on replisome disassembly, which we discovered was regulated by coupling ubiquitin to one of the core replisome components. We found that yeast and animal cells use different enzymes to control this process, yet replisome disassembly is controlled in a very similar manner in both cases. Whereas one strand of the DNA duplex at replication forks passes through the centre of the helicase that is at the heart of the replisome, the other parental DNA strand is excluded from the helicase and prevents binding of the ubiquitin ligase to its target site on the replisome until DNA replication termination. In our ongoing research, we study additional enzymes and new pathways that regulate this process in animal cells, either in response to defects in chromosome replication or when cells enter mitosis before genome duplication has been completed.

Most recently, we have started to study the process of replisome assembly during DNA replication initiation in animal cells, based on our identification of an essential assembly factor that is mutated in human disease and is not present in yeasts (where the mechanism of replisome assembly had been studied in most detail until now). Much remains to be learned about this process, and the mechanism of metazoan replisome assembly will be an important focus of our work in the years ahead.

A deeper understanding of replisome assembly and disassembly will help us to understand how cells normally preserve genome integrity, as well as providing new insights into how inherent replication defects in human cancer could be exploited therapeutically.

 

Selected Publications

  • 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. 
  • 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.
  • Fujisawa R., Polo Rivera C., Labib K (2022) Multiple UBX proteins reduce the ubiquitin threshold of the mammalian Elife 11 doi:10.7554/eLife.76763 PMID: 35920641
  • Evrin C, Serra-Cardona A, Duan S, Mukherjee PP, Zhang Z, Labib KPM (2022) Spt5 histone binding activity preserves chromatin during transcription by RNA polymerase II EMBO Journal 41 1-14 doi:10.15252/embj.2021109783 PMID: 35102600
  • 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
  • Canal B, Fujisawa R, McClure AW, Deegan TD, Wu M, Ulferts R, Weissmann F, Drury LS, Bertolin AP, Zeng J, Beale R, Howell M, Labib K, Diffley JFX (2021) Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease Biochemical Journal 478 2465-2479 doi:10.1042/BCJ20210199 PMID: 34198324
  • Lim CT, Tan KW, Wu M, Ulferts R, Armstrong LA, Ozono E, Drury LS, Milligan JC, Zeisner TU, Zeng J, Weissmann F, Canal B, Bineva-Todd G, Howell M, O'Reilly N, Beale R, Kulathu Y, Labib K, Diffley JFX (2021) Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease Biochemical Journal 478 2517-2531 doi:Free PMC article PMID: 34198325
  • Canal B, McClure AW, Curran JF, Wu M, Ulferts R, Weissmann F, Zeng J, Bertolin AP, Milligan JC, Basu S, Drury LS, Deegan TD, Fujisawa R, Roberts EL, Basier C, Labib K, Beale R, Howell M, Diffley JFX (2021) Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease Biochemical Journal 478 2445-2464 doi:10.1042/BCJ20210198 PMID: 34198326
  • Milligan JC, Zeisner TU, Papageorgiou G, Joshi D, Soudy C, Ulferts R, Wu M, Lim CT, Tan KW, Weissmann F, Canal B, Fujisawa R, Deegan T, Nagaraj H, Bineva-Todd G, Basier C, Curran JF, Howell M, Beale R, Labib K, O'Reilly N, Diffley JFX (2021) Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease Biochemical Journal 478 2499-2515 doi:10.1042/BCJ20210197 PMID: 34198327
  • Basu S, Mak T, Ulferts R, Wu M, Deegan T, Fujisawa R, Tan KW, Lim CT, Basier C, Canal B, Curran JF, Drury LS, McClure AW, Roberts EL, Weissmann F, Zeisner TU, Beale R, Cowling VH, Howell M, Labib K, Diffley JFX (2021) Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase Biochem J 478 2481-2497 doi:10.1042/BCJ20210219 PMID: 34198328
  • 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
  • Mukherjee, P & Labib, K (2019) In vitro reconstitution defines the minimal requirements for Cdc48-dependent disassembly of the CMG helicase in budding yeast Cell Rep.  28 2777-2783 doi:10.1016/j.celrep.2019.08.026
  • 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
View full research profile and publications

Teaching

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 leads an MRC-funded project within MRC PPU, to assess our carbon footprint of SLS and seek to reduce the environmental impact of our research.

Media availability

I am available for media commentary on my research.

Chromosome replication and genome integrity

Contact Corporate Communications for media enquiries.

Areas of expertise

  • Cancer

Awards

Award Year
Major Personal Funding Awards / CRUK Programme Discovery Award 2023
Fellow of the Royal Society of Edinburgh 2016
Major Personal Funding Awards / CRUK Programme Discovery Award   2016
Major Personal Funding Awards / Wellcome Investigator Award 2013
Member of the European Molecular Biology Organisation 2010
National Sciences Prizes awarded since 1990 / British Society of Cell Biology Hooke Medal 2010

Stories

News

Life Sciences researcher Professor Karim Labib has been awarded £2million to explore the role that one of the most fundamental processes in cell biology plays in cancer.

Published on 18 September 2017