The role of circadian gene timeless in gastrointestinal cancers

Timeless is an evolutionarily preserved protein involved in the circadian rhythm of melanogaster flies while its role in mammalian circadian clock systems has not been fully elucidated. Timeless is deemed essential to protect genomic replication and stability. Destruction of timeless in the rat suprachiasmatic nucleus disrupted the rhythm of suprachiasmatic neural activity, reducing PER1, PER2, and PER3 and increasing cryptochrome CRY1 and CRY2. In addition, the full-length timeless protein showed a 24-hour fluctuation, while a truncated isoform was substantially expressed, indicating the active role of mammals timeless in the circadian clock system. Timeless is also involved in DNA replication, telomere length, genome integrity maintenance, and ATM/ATR signaling pathway regulation. Recent studies have shown that timeless interacts with poly (ADP ribose) polymerase 1 and regulates homologous recombination pathways and non-homologous end-binding pathways, both of which are required to repair double-stranded DNA fractures. Recently, it has been reported that timeless is regulated in different types of human tumors and is involved in the development and progression of cancer. Studies showed that timeless, a factor involved in DNA repair, is overexpressed in cancerous tissues and is essential for the proliferation of tumor cells. Timeless knockdown inhibits tumor growth, induces apoptosis and aging, and disrupts the DNA repair pathway in cancer cells. Therefore, timeless can be a promising diagnostic marker and an effective strategy for cancer treatment. However, more clinical research is needed to achieve many achievements in this field.