Per1, short for Period circadian regulator 1, is a core component of the circadian clock system. 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 [9]. The circadian clock regulated by Per1 is involved in numerous biological processes, including metabolism, cell proliferation, and immune response, and is closely associated with various diseases [1-10].

In trastuzumab-resistant HER2-positive gastric cancer cells, the circadian oscillation of HK2-dependent glycolysis is regulated by a transcriptional complex containing PER1, and silencing PER1 disrupts this rhythm and reverses trastuzumab resistance [1]. In pancreatic cancer, ALKBH5 post-transcriptionally activates PER1 via m6A demethylation in an m6A-YTHDF2-dependent manner, and PER1 upregulation reactivates ATM-CHK2-P53/CDC25C signalling to inhibit cell growth [2]. In ocular melanoma, YTHDF2 recognizes m6A-modified PER1 mRNA and promotes its degradation, accelerating tumorigenesis [3]. In mice, Per1 deficiency leads to enhanced negative masking responses, suggesting that Per1 suppresses such responses [4]. In polycystic ovary syndrome, PER1 promotes granulosa cell ferroptosis and dysfunctional lipid metabolism by inhibiting the SREBF2/ALOX15 axis [5]. In Per1-deficient mice, the daily oxygen consumption rhythm is deregulated, and mitochondrial dynamics and GPx-related ROS fluctuations are impaired [6]. In rat mandibular condylar chondrocytes, PER1 can regulate the expression of MMP13 through the NF-κB pathway, affecting the progression of temporomandibular osteoarthritis [7]. Overexpression of PER1 in mice with hindlimb ischemia promotes functional recovery by regulating macrophage polarization [8]. In rats, WNK3 can phosphorylate PER1 to promote its degradation, affecting the circadian rhythm in the suprachiasmatic nucleus [9]. In ovarian cancer, PER1 expression is lower in various subtypes compared to normal ovarian tissue, and its expression level is related to prognosis and immune infiltration [10].

In conclusion, Per1 is crucial for maintaining circadian rhythm and regulating multiple biological processes. Gene-knockout (KO) or conditional-knockout (CKO) mouse models have been instrumental in revealing its role in various disease conditions such as cancer, polycystic ovary syndrome, and temporomandibular osteoarthritis, providing insights into disease mechanisms and potential therapeutic targets.

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. Yu, Jie, Chai, Peiwei, Xie, Minyue, Fan, Xianqun, Jia, Renbing. 2021. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. In Genome biology, 22, 85. doi:10.1186/s13059-021-02308-z. https://pubmed.ncbi.nlm.nih.gov/33726814/

4. 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/

5. 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/

6. Sun, Qi, Yang, Yunxia, Wang, Zhongqiu, Wang, Junsong, Zhang, Jianfa. 2020. PER1 interaction with GPX1 regulates metabolic homeostasis under oxidative stress. In Redox biology, 37, 101694. doi:10.1016/j.redox.2020.101694. https://pubmed.ncbi.nlm.nih.gov/32896721/

7. 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/

8. 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/

9. 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/

10. Chen, Mali, Zhang, Lili, Liu, Xiaolong, Ma, Zhen, Lv, Ling. 2021. PER1 Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Ovarian Cancer. In Frontiers in genetics, 12, 697471. doi:10.3389/fgene.2021.697471. https://pubmed.ncbi.nlm.nih.gov/34220965/