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.
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