Study discovers new process for cells to repair DNA damage

Reporting their finding in Cell, the researchers describe a new process in DNA repair in which cells remove harmful DNA-protein lesions from a cell’s nucleus, ensuring the stability of their genetic material and promoting cell survival. The team calls this new process nucleophagy.

Nucleophagy is a natural cellular cleaning mechanism known as autophagy that is essential for repairing DNA and ensuring cell survival. It involves a commonly expressed protein called TEX264.

In a patient receiving chemotherapy for colorectal cancer, the drugs cause DNA lesions to form. In response, the body expresses TEX264, which activates the nucleophagy process, guiding the lesions to the cell’s waste disposal system, where they are broken down and destroyed.

The research team used advanced techniques, including biochemical, cell biological and bioinformatics tools, zebrafish animal model and colorectal cancer patient materials, to confirm that nucleophagy is crucial for repairing damaged DNA.

DNA (in blue) and the nuclear envelope (in green) found in the nuclei of cancer cells are attacked by the lysosomes (in red) after exposure to chemotherapy drugs as part of the nucleophagy-orchestrated DNA repair process.

This study provides insights into a new pathway for cells to repair DNA damage, which could improve cancer treatments and lead to better outcomes for patients in future, say the researchers.

Lead investigator Kristijan Ramadan, Medical Research Council Investigator at the Department of Oncology, Oxford, and Toh Kian Chui Distinguished Professor in Cancer and Stem Cell Biology and Director of Cancer Discovery and Regenerative Medicine Programme at Lee Kong Chian School of Medicine (LKCMedicine), NTU Singapore, said: 'While autophagy is known to be associated with DNA repair, there has been no evidence of its direct role in the repair of DNA lesions until now. Our discovery that nucleophagy plays a direct role in DNA repair of chemotherapy-induced lesions is the result of a five-year joint effort among several laboratories in the UK, Singapore, USA, Portugal and Croatia.'

Patients with high levels of TEX264 have better responses to cancer treatment.

In particular, the research team says the findings are significant for patients with colorectal cancer – the second leading cause of cancer-related deaths worldwide, according to the World Health Organisation.

An analysis of colorectal cancer patients treated with Topoisomerase 1 inhibitors, such as FOLFIRI therapy (a common chemotherapy used to treat colorectal cancer), showed that patients with high levels of TEX264 in their tumours have a 50 per cent better response to treatment compared to those with low levels of TEX264.

First author of the study, Oxford’s Oncology DPhil student Pauline Lascaux, said: 'This novel mechanism of DNA damage repair helps us comprehend how our cells maintain genetic integrity and respond to cancer treatments. This breakthrough opens avenues for a better understanding of how our body protects genetic material and how we can enhance the efficacy of cancer therapies for patients. I believe that modulating autophagy activity is the key to overcoming resistance to therapy in colorectal cancer.'

In future studies, the research team will explore the role of nucleophagy in the body’s response to chemotherapeutic drugs for other cancers, to see if their discovery is further validated.

The team’s ultimate goal is to use this discovery to improve current chemotherapy responses for cancer patients.

The full paper, 'TEX264 drives selective autophagy of DNA lesions to promote DNA repair and cell survival', is published in Cell.