Puck Knipscheer is professor by special appointment of Biochemistry of Genome Maintenance at the Department of Human Genetics of the Leiden University Medical Center (LUMC). She is also group leader at the Hubrecht Institute (KNAW) and the Oncode Institute.

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Puck Knipscheer is professor by special appointment of Biochemistry of Genome Maintenance at the Department of Human Genetics of the Leiden University Medical Center (LUMC). She is also group leader at the Hubrecht Institute (KNAW) and the Oncode Institute.

Molecular mechanisms of genome maintenance

Research in the Knipscheer lab is focussed on the molecular details of genome maintenance pathways. We are specifically interested in processes that are coupled to DNA replication. Therefore, we make use of the Xenopus egg extract system that supports highly regulated vertebrate DNA replication, and replication-linked processes, in vitro. This powerful biochemical system is combined with mass spectrometry, high-throughput sequencing, and biochemical, biophysical and cell biological approaches to gain insights into the molecular details of processes that occur at the replication fork to maintain genome integrity. Currently, we focus on understanding how DNA interstrand crosslinks (ICLs) are repaired, and how stable alternative DNA structures are resolved. ICLs are highly toxic DNA lesions that can form endogenously but are also induced at high doses in cancer chemotherapy. The major crosslink repair pathway is the DNA replication-coupled Fanconi anemia pathway, affected in the cancer predisposition disorder Fanconi anemia (FA). While our mechanistic knowledge of the FA pathway is increasing, many aspects remain unknown. Furthermore, while the FA pathway was long thought to be the only ICL repair pathway, we recently identified a new pathway that repairs ICLs induced by endogenous aldehydes of which we are currently deciphering the mechanism. In addition, we are very much interested in the mechanisms that regulate the unwinding of mutagenic alternative DNA structures, specifically G-quadruplex (or G4) structures, during DNA replication. We have recently identified a multistep mechanism, involving two accessory helicases, that resolves G4s coupled to DNA replication. We are defining how this mechanism is regulated and are investigating other mechanisms that resolve G4 structures to keep our genome safe.

Academic career

Puck Knipscheer studied Molecular Sciences at the Wageningen University and specialized in Molecular Biology and Biochemistry. She performed her PhD research at the Netherlands Cancer Institute under supervision of Prof. Dr. Titia Sixma. She used X-ray crystallography and biochemistry to decipher mechanisms of posttranslational modification by SUMO. In 2007 she obtained her PhD cum laude from the Erasmus University in Rotterdam based on her thesis entitled ‘Regulation of SUMO modification’. For her postdoc she moved to the laboratory of Prof. Dr. Johannes Walter at Harvard Medical School in Boston. Here, she started using the Xenopus egg extract system to study the repair of DNA interstrand crosslinks (ICLs) and showed how the Fanconi anemia pathway acts in a specific step of this process. In 2011 she returned to The Netherlands where she started her research group at the Hubrecht Institute (KNAW) in Utrecht. In 2017 her group joined the Oncode Institute and in 2023 Knipscheer was appointed professor of Biochemistry of Genome Maintenance at the Human Genetics Department of the LUMC.

Knipscheer received several personal grants for her research including a KWF grant, Vidi and Vici grants (NWO), and an ERC consolidator grant. For her PhD and postdoctoral research, she was awarded the Heineken Young Scientist Award for Biochemistry and Biophysics (2010).