The project aims to uncover fundamental mechanisms that help preserve healthy cell function, with potential relevance for cancer treatment, therapy resistance and long-term side effects in cancer survivors.

The European Research Council has announced the winners of its latest Advanced Grant competition. These prestigious grants support established research leaders in pursuing ambitious, curiosity-driven projects that could lead to major scientific breakthroughs.

Every day, the DNA in our cells is damaged by environmental factors, normal cellular metabolism and, importantly, by many DNA-damaging chemotherapies that remain a cornerstone of cancer treatment. When such DNA lesions block the process by which genes are transcribed, cells experience transcription stress. If this stress is not resolved, it can disrupt gene expression and cellular homeostasis, contributing to cellular dysfunction, senescence and cell death.

With his ERC Advanced Grant project GeneGuard: Uncovering the Mechanisms that Safeguard Transcription, Oncode Investigator Jurgen Marteijn will investigate how cells respond to this type of stress through a specialised set of DNA repair pathways known as transcription-coupled repair.

“These repair pathways are essential because they operate directly on actively transcribed genes,” says Jurgen Marteijn. “With GeneGuard, we want to understand how cells recognise transcription stress and how they coordinate the repair mechanisms needed to restore normal gene activity.”

Recent work from the Marteijn laboratory has revealed previously unknown transcription-coupled repair mechanisms. Additional findings suggest that the persistence of  DNA damage-stalled RNA polymerase II, rather than DNA damage alone, is a key driver of cellular dysfunction.

These findings are highly relevant in the context of cancer. Many widely used chemotherapies work by damaging DNA in cancer cells. Transcription-coupled repair may therefore play a dual role: it can help tumour cells survive therapy-induced DNA damage and contribute to treatment resistance, but it is also essential for protecting healthy cells and maintaining tissue function.

This balance is particularly important in non-dividing cells, such as neurons, where several genome-wide DNA repair pathways are less active. In these cells, transcription-coupled repair may be a primary defence against transcription-blocking DNA damage. Better understanding these mechanisms could therefore provide new insights into chemotherapy-induced peripheral neuropathy, cognitive impairment, sometimes referred to as “chemobrain”, and accelerated ageing in cancer survivors.

GeneGuard will combine a wide range of advanced approaches, from single-molecule imaging to brain organoids and mouse models. By uncovering the molecular mechanisms that detect, signal and resolve transcription stress, the project will provide fundamental insights into how cells protect transcription after DNA damage.

“This ERC Advanced Grant allows us to address a fundamental biological question with direct relevance to cancer and human health,” says Marteijn. “If we understand how cells safeguard transcription, we can also better understand why some cells recover from DNA damage while others fail.”

For Oncode Institute, the award underlines the importance of curiosity-driven fundamental cancer research.

About ERC Advanced Grants
ERC Advanced Grants are awarded by the European Research Council to outstanding, established research leaders with a track record of significant research achievements. The grants enable researchers to pursue ambitious, high-risk, high-gain projects at the frontiers of knowledge.