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Genes that regulate the circadian clock in mammals, such as period 1 (PER1), might function as a tumor-suppressors.

Women who work at night have an increased risk of developing breast or colon cancer, which could be evidence that disruption of our circadian rhythm upsets more than just our sleep patterns. The genes that regulate the circadian clock in mammals have recently been identified, and Sigal Gery and colleagues now show that one of these genes, period 1 (PER1), might function as a tumour-suppressor gene.

Given the established link between circadian rhythms and the DNA-damage response, the authors investigated the response to ionizing radiation (IR) of colorectal cancer cell lines that overexpress PER1. The authors showed that overexpression of PER1 induced high expression levels of p53 that were only slightly increased after treatment with IR. Despite p53 expression, these cells did not have increased expression of p21, the cyclin-dependent-kinase inhibitor that mediates p53-induced cell-cycle arrest after DNA damage. This is because, after IR, PER1 overexpression results in the increased expression of the oncoprotein MYC, which is known to inhibit p21 expression and induce apoptosis. Therefore, cells that expressed PER1 were less able to arrest in G2/M and had higher rates of apoptosis than control cells.

Given that PER1 seems to be important for the cellular response to IR, does it interact with other proteins that regulate this pathway? Co-immunoprecipitation experiments showed that PER1 can interact with the DNA-damage-response kinase, ataxia telangiectasia mutated (ATM), and the checkpoint protein CHK2. The authors propose that PER1 might facilitate the activation of ATM or might function as an adaptor protein that recruits other proteins that are required for the ATM-mediated response to DNA damage.

Overexpression of PER1 in various cancer cell lines inhibited clonogenic growth as well as anchorage-independent growth, which further indicates that PER1 might function as a tumour suppressor. So the authors investigated whether PER1 expression is altered in human cancer. Reverse transcriptase-PCR analyses showed that 70% of human non-small-cell lung cancer samples and 46% of human breast cancer samples had reduced expression levels of PER1 compared with controls.

These results further increase our preliminary understanding of how the circadian clock regulates pathways that are crucial for the suppression of malignant growth.

Nicola McCarthy

References

Gery, S. et al. The circadian gene Per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol. Cell 22 375–382 (2006) | Article | PubMed |