New grant to help strengthen cancer treatment
Professor Michael Lund Nielsen from the Department of Molecular Biology and Genetics at Aarhus University has received a grant of DKK 3.9 million from the Danish Cancer Society. The grant will support research into how cancer cells’ handling of DNA damage can be exploited to develop more targeted treatment strategies.
The project focuses on the protein PARP1, which monitors DNA integrity while the cell copies its genetic material. This is particularly important in cancer cells, which often divide rapidly and are therefore especially dependent on efficient mechanisms for managing DNA damage.
Michael Lund Nielsen and his research group have shown that PARP1 does more than help detect DNA damage. The protein also regulates itself through a chemical modification known as auto-ADP-ribosylation. This modification changes the properties of PARP1 and appears to be crucial for determining when the protein is released from DNA. If PARP1 is not released correctly, it can block normal DNA replication and create additional stress in the cell.
The researchers will investigate how this mechanism affects the stress that arises when cancer cells copy their DNA, and how it can be used to improve the effect of existing PARP inhibitors, which are currently used to treat several types of cancer.
“This has been a long development process, and with the technologies we now have, we can hopefully help improve patient treatment in the future,” says Professor Michael Lund Nielsen.
Among other approaches, the research group will use advanced mass spectrometry to map the chemical modifications on PARP1. Mass spectrometry makes it possible to measure the structure, mass and quantity of molecules with high precision, making it a central tool in the project.
“We have developed a mass spectrometric strategy that makes it possible to precisely identify the amino acids in PARP1 that are modified with ADP-ribose. There has long been uncertainty in the field about exactly where PARP1 is modified, and how these modifications help regulate the protein’s interaction with DNA during replication of the genetic material. Our technology provides an unprecedented opportunity to systematically map these modifications and understand their biological significance,” explains Michael Lund Nielsen.
The aim is to gain a better understanding of why some cancer cells respond to treatment with PARP inhibitors, while others develop resistance. In the longer term, the project may help identify new biomarkers and point towards more precise combination treatments for cancer patients.
The grant therefore supports research that can bring fundamental knowledge about DNA repair and replication stress closer to the cancer treatments of the future.