A team of researchers from the Andalusian Centre for Molecular Biology and Regenerative Medicine (CABIMER) and the University of Seville, in collaboration with the Virgen Macarena University Hospital, have identified a fundamental mechanism that links the 24-hour circadian cycle to the precise repair of DNA breaks. This study, which focused on the circadian protein Cryptochrome1 (CRY1), suggests that the time of day when radiotherapy is administered can significantly influence the effectiveness of treatment for certain types of cancer.

The rate of DNA repair

Maintaining genomic stability is essential to prevent the onset of cancer. It is therefore important that DNA breaks are repaired as accurately as possible. Indeed, it is relatively common for cancer cells to be unable to repair their DNA efficiently. Consequently, multiple cancer treatments, such as radiotherapy, exploit this weakness by generating DNA breaks that tumour cells are unable to repair.

This study shows that DNA break repair in human cells exhibits a circadian oscillation. In other words, its efficiency is not homogeneous, but varies cyclically depending on the time of day. In a normal human cycle, repair activity peaks in the early morning and then decreases gradually until nightfall, subsequently increasing again during the night.

The CRY1 protein acts as a brake on repair

Our research has identified that this regulation depends on a central component of the biological clock, namely the CRY1 protein. This protein acts as a timer and its abundance changes naturally during the day/night cycle. In fact, the repair process reacts directly to CRY1 levels.

When CRY1 levels are low (corresponding to early morning in humans), efficient DNA repair is stimulated. Conversely, when CRY1 levels increase (which occurs naturally in the afternoon/evening), repair is reduced, thereby increasing the sensitivity of cells to DNA-breaking agents such as ionising radiation.

Implications for cancer and chronotherapy

This circadian regulation has a direct impact on cancer progression and response to radiotherapy in specific tumours. Our study findings suggest that the reduction in repair that occurs when CRY1 levels are high can be exploited therapeutically.

Thus, breast cancer patients with tumours expressing higher levels of CRY1 were found to be more sensitive to radiotherapy. In addition, a retrospective analysis of patient data from the Virgen Macarena University Hospital revealed a significant difference in overall survival based on the time of irradiation: treatment in the afternoon/evening, when CRY1 levels are naturally higher, made tumour samples more sensitive to radiotherapy and improved patient prognosis. This effect was also observed in patients with prostate cancer and breast cancer, but not in lung cancer or gliomas. Therefore, these findings open the door to exploring the therapeutic potential of irradiation at specific times of the day, a phenomenon known as chronoradiotherapy.