Professor Genome Stability
Marcel Tijsterman is professor of Genome Stability at the Human Genetics Department of the Leiden University Medical Center (LUMC). He is also visiting professor of Genome Engineering at the Institute of Biology Leiden (IBL).
Marcel Tijsterman is professor of Genome Stability at the Human Genetics Department of the Leiden University Medical Center (LUMC). He is also professor of Genome Engineering at the Institute of Biology Leiden (IBL).
The human body is of dazzling complexity. It is build-up by ~ ten to the power fourteen cells. Yet all these cells, whether they are neuronal, muscle or skin cells, contain the same genetic information that is stored in a molecule named DeoxyriboNucleic Acid (DNA). The information is organized in 23 pairs of chromosomes and written in a language that only has 4 letters: the bases G, A, T and C. Each human cell contains 12 billion of these letters. Together, the 46 chromosomes are referred to as the human genome - the genome, defined as the complement of genetic material that makes up an organism. The chair “Genome Stability” is concerned with the stability of genetic content and the maintenance and repair of DNA, which is essential to safeguard genetic integrity and prevent disease.
While the necessity to carefully transmit genetic information to progeny (or daughter cells upon cell division) is obvious, we will personally, or in the people surrounding us, experience the fact that this process is not without error. Mutations resulting from errors during DNA replication, or resulting from copying or mis-repair of damaged DNA will accumulate during our lifetime and cause the disease that is responsible for a quarter of all deaths in the Western world: cancer. Although cancer is conceptually a simple disease (i.e. the mis-regulation of cells leading to uncontrolled proliferation in otherwise hostile environments or conditions), the treatment is highly complex as each tumor has a different genetic make-up and consists of cells that have the ability to mutate and adapt. It is foreseen that future cancer therapies are therefore very much personalized and are guided by genomic information derived from tumor cells.
Marcel Tijsterman studied Chemistry at the Leiden University, specializing in Molecular Genetics. He received his PhD in 1999 studying “Repair analysis of UV-induced DNA damage at nucleotide resolution”. For his postdoctoral work, he joined the lab of Ronald Plasterk at the Netherlands Cancer Institute in Amsterdam, which moved to the Hubrecht Institute in Utrecht in 2001. There he started his independent research on genomic instability and DNA damage responses. In 2009, he moved his research group to the Leiden University Medical Center (LUMC), where he was appointed professor in 2014. The title of his inaugural lecture was: “On Darwin and DNA, and on beauty in decay”. In 2017, he was also appointed professor of Genome Engineering at the Institute of Biology Leiden (IBL)
At the LUMC, Tijsterman’s research group is embedded in the LUMC profile area "Cancer Pathogenesis and Therapy" which entails a multidisciplinary approach aimed to integrate and to translate results of basic research in cancer genetics, molecular cell biology and immunology into precision cancer care. Tijsterman focusses on understanding and exploiting the mechanisms that cause genome instability and mutagenesis. A particular focus is on the how cells deal with obstructions to efficient and accurate DNA replication, such as thermodynamically stable secondary structures (e.g. G-quadruplexes) and damaged bases.
At the IBL, the research is aimed towards understanding and exploiting the roles of DNA repair mechanisms in current and future genome engineering strategies, with a special focus on plant biotechnology and crop development.
Some key discoveries are: i) that cells employ an alternative mechanism to repair DNA breaks that result from replication fork obstacles, which was termed polymerase Theta-Mediated End Joining (TMEJ), as it critically depends on the functionality of the A-family polymerase Theta; ii) that TMEJ is a key driver of random integration of DNA in mammalian cells, a phenomenon also known as illegitimate recombination ; iii) the identification of the mechanism by which plant cells incorporate foreign DNA into their genome, a process underlying transgenesis; iv) the genetic dissection of the repair pathways responsible for CRISPR-mediated gene editing.
While the primary aim of this basic research is to provide mechanistic insight into the processes that are responsible for the maintenance of genome integrity and how these processes protect against tumor development, a number of clinically relevant implications have been identified for cancer as well as for gene-correction applications. These are subject of ongoing investigation.
Prizes and honourable appointments
Marcel Tijsterman received career development support from NWO (VIDI) and ERC.
Professor Genome Stability
- Faculteit Geneeskunde
- Divisie 4
- Humane Genetica
- Kamp J.A., Lemmens B.B.L.G., Romeijn R.J., Changoer S.C., Schendel R. van & Tijsterman M. (2021), helicase q promotes homology-driven dna double-strand break repair and prevents tandem duplications, Nature Communications (12): 7126 .
- Tol N. van, Schendel R. van, Bos. A, Kregten M. van, Pater S. de, Hooykaas P.J.J. & Tijsterman M. (2021), gene targeting in polymerase theta-deficient arabidopsis thaliana, Plant Journal 109(1): 112-125.
- Schimmel, J.; Munoz-Subirana, N.; Kool, H.; Schendel, R. van & Tijsterman, M. (2021), Small tandem DNA duplications result from CST-guided Pol alpha-primase action at DNA break termini, Nature Communications 12(1).
- Zatreanu, D.; Robinson, H.M.R.; Alkhatib, O.; Boursier, M.; Finch, H.; Geo, L.; Grande, D.; Grinkevich, V.; Heald, R.A.; Langdon, S.; Majithiya, J.; McWhirter, C.; Martin, N.M.B.; Moore, S.; Neves, J.; Rajendra, E.; Ranzani, M.; Schaedler, T.; Stockley, M.; Wiggins, K.; Brough, R.; Sridhar, S.; Gulati, A.; Shao, N.; Badder, L.M.; Novo, D.; Knight, E.G.; Marlow, R.; Haider, S.; Callen, E.; Hewitt, G.; Schimmel, J.; Prevo, R.; Alli, C.; Ferdinand, A.; Bell, C.; Blencowe, P.; Bot, C.; Calder, M.; Charles, M.; Curry, J.; Ekwuru, T.; Ewings, K.; Krajewski, W.; MacDonald, E.; McCarron, H.; Pang, L.; Pedder, C.; Rigoreau, L.; Swarbrick, M.; Wheatley, E.; Willis, S.; Wong, A.C.; Nussenzweig, A.; Tijsterman, M.; Tutt, A.; Boulton, S.J.; Higgins, G.S.; Pettitt, S.J.; Smith, G.C.M. & Lord, C.J. (2021), Pol theta inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance, Nature Communications 12(1).
- Schendel, R. van; Romeijn, R.; Buijs, H. & Tijsterman, M. (2021), Preservation of lagging strand integrity at sites of stalled replication by Pol alpha-primase and 9-1-1 complex, Science Advances 7(21).
- Kamp, J.A.; Schendel, R. van; Dilweg, I.W. & Tijsterman, M. (2020), BRCA1-associated structural variations are a consequence of polymerase theta-mediated end-joining, Nature Communications 11(1).
- Bostelen, I. van; Schendel, R. van; Romeijn, R. & Tijsterman, M. (2020), Translesion synthesis polymerases are dispensable for C. elegans reproduction but suppress genome scarring by polymerase theta-mediated end joining, PLOS GENETICS 16(4).
- Zelensky, A.N.; Schoonakker, M.; Brandsma, I.; Tijsterman, M.; Gent, D.C. van; Essers, J. & Kanaar, R. (2020), Low dose ionizing radiation strongly stimulates insertional mutagenesis in a gamma H2AX dependent manner, PLOS GENETICS 16(1).
- Schimmel, J.; Schendel, R. van; Dunnen, J.T. den & Tijsterman, M. (2019), Templated Insertions: A Smoking Gun for Polymerase Theta-Mediated End Joining, Trends in Genetics 35(9): 632-644.
- Schimmel, J.; Kool, H.; Schendel, R. van & Tijsterman, M. (2017), Mutational signatures of non-homologous and polymerase theta-mediated end-joining in embryonic stem cells, EMBO Journal 36(24): 3634-3649.
- Zelensky, A.N.; Schimmel, J.; Kool, H.; Kanaar, R. & Tijsterman, M. (2017), Inactivation of Pol theta and C-NHEJ eliminates off-target integration of exogenous DNA, Nature Communications 8.
- Bostelen, I. van & Tijsterman, M. (2017), Combined loss of three DNA damage response pathways renders C-elegans intolerant to light, DNA Repair 54: 55-62.
- Zeller, P.; Padeken, J.; Schendel, R. van; Kalck, V.; Tijsterman, M. & Gasser, S.M. (2016), Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability, Nature Genetics 48(11): 1385-1395.
- Kregten M. van, Pater B.S. de, Romeijn R., Schendel R. van, Hooykaas P.J.J. & Tijsterman M. (2016), T-DNA integration in plants results from polymerase-theta-mediated DNA repair, Nature Plants 2(10): 16164.
- Schendel, R. van; Heteren, J. van; Welten, R. & Tijsterman, M. (2016), Genomic Scars Generated by Polymerase Theta Reveal the Versatile Mechanism of Alternative End-Joining, PLoS Genetics 12(10).
- Kregten, M. van; Pater, S. de; Romeijn, R.; Schendel, R. van; Hooykaas, P.J.J. & Tijsterman, M. (2016), T-DNA integration in plants results from polymerase-theta-mediated DNA repair, Nature Plants 2(10).
- Koning, M.T.; Bergen, C.A.M. van; Trollmann, I.J.M.; Scherer, H.U.; Attikum, H. van; Toes, R.E.M.; Kielbasa, S.M.; Tijsterman, M. & Veelken, H. (2016), Prevalence, structure and putative mechanism for large genetic insertions in VDJ recombination, European Journal of Immunology 46: 1136-1136.
- Tijsterman M. (5 February 2016), Over Darwin en DNA, over schoonheid in vergankelijkheid (Inaugural address, Science, Leiden). Leiden: Universiteit Leiden.
- Kregten M. van, Pater S. de, Romeijn R., Schendel R. van, Hooykaas P.J.J. & Tijsterman M. (2016), DNA integration in plants results from polymerase mediated DNA repair, Nature Plants 2: 16164.
- Lemmens, B.; Schendel, R. van & Tijsterman, M. (2015), Mutagenic consequences of a single G-quadruplex demonstrate mitotic inheritance of DNA replication fork barriers, Nature Communications 6.
- Schendel, R. van; Roerink, S.F.; Portegijs, V.; Heuvel, S. van den & Tijsterman, M. (2015), Polymerase Theta is a key driver of genome evolution and of CRISPR/Cas9-mediated mutagenesis, Nature Communications 6.
- Kregten, M. van & Tijsterman, M. (2014), The repair of G-quadruplex-induced DNA damage, Experimental Cell Research 329(1): 178-183.
- Bosch, P.C.; Segura-Bayona, S.; Koole, W.; Heteren, J.T. van; Dewar, J.M.; Tijsterman, M. & Knipscheer, P. (2014), FANCJ promotes DNA synthesis through G-quadruplex structures, EMBO Journal 33(21): 2521-2533.
- Koole, W. & Tijsterman, M. (2014), Mosaic analysis and tumor induction in zebrafish by microsatellite instability-mediated stochastic gene expression.
- Roerink, S.F.; Schendel, R. van & Tijsterman, M. (2014), Polymerase theta-mediated end joining of replication-associated DNA breaks in C.elegans, Genome Research 24(6): 954-962.
- Koole, W.; Schendel, R. van; Karambelas, A.E.; Heteren, J.T. van; Okihara, K.L. & Tijsterman, M. (2014), A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites, Nature Communications 5.
- Schendel, R. van & Tijsterman, M. (2013), Microhomology-Mediated Intron Loss during Metazoan Evolution, Genome Biology and Evolution 5(6): 1212-1219.
- Waaijers, S.; Portegijs, V.; Kerver, J.; Lemmens, B.B.L.G.; Tijsterman, M.; Heuvel, S. van den & Boxem, M. (2013), CRISPR/Cas9-Targeted Mutagenesis in Caenorhabditis elegans, Genetics 195(3): 1187-+.
- Tarsounas, M. & Tijsterman, M. (2013), Genomes and G-Quadruplexes: For Better or for Worse, Journal of Molecular Biology 425(23): 4782-4789.
- Koole, W.; Schafer, H.S.; Agami, R.; Haaften, G. van & Tijsterman, M. (2013), A versatile microsatellite instability reporter system in human cells, Nucleic Acids Research 41(16).
- Johnson, N.M.; Lemmens, B.B.L.G. & Tijsterman, M. (2013), A Role for the Malignant Brain Tumour (MBT) Domain Protein LIN-61 in DNA Double-Strand Break Repair by Homologous Recombination, PLoS Genetics 9(3).
- Lemmens, B.B.L.G.; Johnson, N.M. & Tijsterman, M. (2013), COM-1 Promotes Homologous Recombination during Caenorhabditis elegans Meiosis by Antagonizing Ku-Mediated Non-Homologous End Joining, PLoS Genetics 9(2).
- Roerink, S.F.; Koole, W.; Stapel, L.C.; Romeijn, R.J. & Tijsterman, M. (2012), A Broad Requirement for TLS Polymerases eta and kappa, and Interacting Sumoylation and Nuclear Pore Proteins, in Lesion Bypass during C. elegans Embryogenesis, PLoS Genetics 8(6): -.
- Lemmens, B.B.L.G. & Tijsterman, M. (2011), DNA double-strand break repair in Caenorhabditis elegans, Chromosoma 120(1): 1-21.
- Pontier DB, Kruisselbrink E, Guryev V & Tijsterman M (2009), Isolation of deletion alleles by G4 DNA-induced mutagenesis, Nature Methods 6(9): 655U43.
- Pontier DB & Tijsterman M (2009), A Robust Network of Double-Strand Break Repair Pathways Governs Genome Integrity during C. elegans Development, Current Biology 19(16): 1384-1388.
- van Haaften G, Romeijn R, Pothof J, Koole W, Mullenders LHF, Pastink A, Plasterk RHA & Tijsterman M (2006), Identification of conserved pathways of DNA-damage response and radiation protection by genome-wide RNAi, Current Biology 16(13).
No relevant ancillary activities