On worms, transgenic plants, and breast cancer patients
Van Leeuwenhoek Lecture on BioScience.
Marcel Tijsterman is Professor of Genome Stability at the Human Genetics Department (LUMC) since 2009 and also of Genome Engineering at the IBL since 2017.
After his study Chemistry (Leiden University) he obtained his PhD at Leiden University, moved to the NKI (Amsterdam) and after that joined the Hubrecht laboratory (Utrecht), before he returned to Leiden.
At the LUMC he focusses on understanding and exploiting the mechanisms that cause genome instability and mutagenesis. A particular focus is on how cells deal with obstructions to efficient and accurate DNA replication, such as thermodynamically stable secondary structures (e.g. G-quadruplexes) and damages.
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.
Genome stability is essential to accurately transmit all genetic information to progeny to safeguard genetic integrity and prevent disease. Unfortunately, all of us (either personally, or in the people surrounding us) will experience the fact that this biology 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.
Our research focusses on understanding and exploiting the mechanisms that prevent or cause genome instability and mutagenesis. In particular, we study how cells deal with obstructions to efficient and accurate DNA replication, such as thermodynamically stable secondary structures (e.g. G-quadruplexes) and damaged bases. These obstacles can lead to chromosomal breaks, which when left unrepaired cause cell death and/or aneuploidy, but in case of inaccurate repair drive carcinogenesis. Using C. elegans as a model system we discovered that cells employ an alternative mechanism to repair DNA breaks that result from replication fork obstacles, which we termed Theta-Mediated End Joining (TMEJ), as it critically depends on the functionality of the A-family polymerase Theta (Koole et al., Nature Commun. 2014; Roerink et al., Genome Res. 2014; Lemmens et al., Nature Commun. 2105; van Schendel et al., PLOS Genet. 2016). We found that TMEJ can repair CRISPR-induced DNA breaks in worms and mammalian cells leading to specific genomic scars that are also observed in congenital disease alleles (van Schendel et al., Nature Commun. 2015; Schimmel et al., EMBO J. 2017). TMEJ is also a key driver of random integration of DNA, a phenomenon also known as illegitimate recombination, in both mammalian cells as well as in plants (Van Kregten et al., Nature Plants 2016, Zelensky et al., Nature Commun. 2017). As such, we serendipitously identified the mechanism that underlies transgenesis in plants, which will be further studied at the Institute Biology Leiden (IBL), in the context of genome engineering strategies to benefit plant biotechnology and crop development. While the primary aim of our 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. Also these are subject of ongoing investigation.
Please keep the following dates free in your diary (all Thursdays at 16 h.):
September 27 - Ton Bisseling (WUR, Molecular Biology)
October 18 - Marta Miaczynska (Warsaw, Inst. of Mol. and Cell Biology)
November 29 - Steven Brown (Zürich, Inst. Pharmacology and Toxicology)