{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPER2 is a central component of the molecular circadian clock that governs ~24‐hour rhythms in physiology and behavior. Multiple studies have demonstrated that alterations in PER2—whether by mutation or by light‐induced transcription—exert profound effects on sleep–wake timing and circadian synchronization. For example, investigations have shown that mutations in PER2 lead to familial advanced sleep phase syndrome and that robust, blue‐light–mediated induction of PER2 in peripheral tissues can be non‐invasively monitored in human leukocytes, underscoring its role in setting daily behavioral patterns and hormonal rhythms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond circadian timing, PER2 has emerged as an important tumor suppressor. Experimental models reveal that PER2 deficiency leads to deregulation of the cell cycle and oncogenes (including c-myc), ultimately promoting tumor formation across a variety of cancers such as breast, colon, gastric, and hematologic malignancies. Moreover, aberrant methylation of the PER2 promoter appears to contribute to its silencing in cancer cells, suggesting that loss of PER2 function can remove a critical checkpoint that normally restrains neoplastic transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPER2 also functions as an integrator of cellular stress responses. Post‐translational modifications—such as phosphorylation by casein kinases—modulate PER2’s stability and nuclear localization, and its physical association with the tumor suppressor p53 helps prevent Mdm2-mediated degradation. These regulatory interactions enable PER2 to influence DNA damage responses and, through reciprocal feedback with factors such as Sirtuin 1, impact aging and cell cycle progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, PER2’s functions extend to diverse peripheral and neurobehavioral systems. Variations in PER2 expression and genetic polymorphisms have been linked not only to cardiac metabolic adaptation and ischemia tolerance but also to mood disorders, seasonal affective disorder, and altered reward processing that underlie addiction. Dysregulation of PER2 in peripheral tissues also correlates with metabolic syndrome features and may even impact gastrointestinal barrier function in alcohol-related liver disease. 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