Per1, short for Period circadian regulator 1, is a core component of the circadian clock. It functions within a feedback loop in the suprachiasmatic nucleus, the primary circadian pacemaker in mammalian brains, to generate a ~24-hour circadian rhythm through transcriptional repression of gene expression [7]. Post-transcriptional modifications of Per1, like phosphorylation by WNK3, can affect its stability, interactions, and thus the circadian rhythm [7].

In trastuzumab-resistant HER2-positive gastric cancer cells, Per1 is part of a transcriptional complex regulating the circadian oscillation of HK2-dependent glycolysis, and silencing Per1 can reverse trastuzumab resistance [1]. In pancreatic cancer, ALKBH5 post-transcriptionally activates Per1 in an m6A-YTHDF2-dependent manner, and Per1 upregulation reactivates ATM-CHK2-P53/CDC25C signalling to inhibit cell growth [2]. In mice, Per1 mutation enhances negative masking responses to light, suggesting it suppresses such responses [3]. In polycystic ovary syndrome, PER1 promotes ferroptosis and lipid metabolism dysfunction in granulosa cells by inhibiting the SREBF2/ALOX15 axis [4]. In hindlimb ischemia, Per1 overexpression promotes functional recovery in mice by regulating macrophage polarization, reducing M1 macrophage polarization and promoting M2 macrophage polarization [6]. In temporomandibular osteoarthritis, PER1 can regulate the expression of MMP13 through the NF-κB pathway in IL-1β-induced mandibular condylar chondrocytes [5].

In summary, Per1 is crucial for maintaining the circadian rhythm. Model-based research, especially through gene knockout models in mice, has revealed its diverse roles in various disease conditions such as cancer, metabolic disorders, and ischemic diseases. Understanding Per1 function can provide new insights into disease mechanisms and potential therapeutic strategies.

References:

1. Wang, Jiao, Huang, Qiong, Hu, Xingbin, Liao, Wangjun, Shi, Min. . Disrupting Circadian Rhythm via the PER1-HK2 Axis Reverses Trastuzumab Resistance in Gastric Cancer. In Cancer research, 82, 1503-1517. doi:10.1158/0008-5472.CAN-21-1820. https://pubmed.ncbi.nlm.nih.gov/35255118/

2. Guo, Xingya, Li, Kai, Jiang, Weiliang, Pan, Qin, Wan, Rong. 2020. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. In Molecular cancer, 19, 91. doi:10.1186/s12943-020-01158-w. https://pubmed.ncbi.nlm.nih.gov/32429928/

3. Milićević, Nemanja, Bergen, Arthur A, Felder-Schmittbuhl, Marie-Paule. 2022. Per1 mutation enhances masking responses in mice. In Chronobiology international, 39, 1533-1538. doi:10.1080/07420528.2022.2126321. https://pubmed.ncbi.nlm.nih.gov/36189750/

4. Chen, Yuanyuan, Liu, Zhaohua, Chen, Hongmei, Fan, Lang, Luo, Man. 2024. Rhythm gene PER1 mediates ferroptosis and lipid metabolism through SREBF2/ALOX15 axis in polycystic ovary syndrome. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167182. doi:10.1016/j.bbadis.2024.167182. https://pubmed.ncbi.nlm.nih.gov/38653359/

5. Wei, Jia-Ming, Tu, Shao-Qin, Wang, Yu-Xuan, Ai, Hong, Chen, Zheng. 2023. Clock gene Per1 regulates rat temporomandibular osteoarthritis through NF-κB pathway: an in vitro and in vivo study. In Journal of orthopaedic surgery and research, 18, 817. doi:10.1186/s13018-023-04301-7. https://pubmed.ncbi.nlm.nih.gov/37907921/

6. Ding, Yang, Wan, Shengyun, Ma, Long, Wei, Kaikai, Ye, Kun. 2023. PER1 promotes functional recovery of mice with hindlimb ischemia by inducing anti-inflammatory macrophage polarization. In Biochemical and biophysical research communications, 644, 62-69. doi:10.1016/j.bbrc.2023.01.001. https://pubmed.ncbi.nlm.nih.gov/36634583/

7. Zhang, Zhao-Huan, Xiong, Jian-Mei, Zhu, Yun-Yi, Zhuang, Jian-Hua, Xu, Xiao-Hui. 2022. WNK3-PER1 interactions regulate the circadian rhythm in the suprachiasmatic nucleus in rats. In American journal of translational research, 14, 1001-1009. doi:. https://pubmed.ncbi.nlm.nih.gov/35273702/