State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China.
Key Laboratory of Algal Biology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China.
Sci Adv. 2023 Sep 29;9(39):eadi7238. doi: 10.1126/sciadv.adi7238.
H3K4 trimethylation (H3K4me3) is a conserved histone modification catalyzed by histone methyltransferase Set1, and its dysregulation is associated with pathologies. Here, we show that Set1 is intrinsically unstable and elucidate how its protein levels are controlled within cell cycle and during gene transcription. Specifically, Set1 contains a destruction box (D-box) that is recognized by E3 ligase APC/C and degraded by the ubiquitin-proteasome pathway. Cla4 phosphorylates serine 228 (S228) within Set1 D-box, which inhibits APC/C-mediated Set1 proteolysis. During gene transcription, PAF complex facilitates Cla4 to phosphorylate Set1-S228 and protect chromatin-bound Set1 from degradation. By modulating Set1 stability and its binding to chromatin, Cla4 and APC/C control H3K4me3 levels, which then regulate gene transcription, cell cycle progression, and chronological aging. In addition, there are 141 proteins containing the D-box that can be potentially phosphorylated by Cla4 to prevent their degradation by APC/C. We addressed the long-standing question about how Set1 stability is controlled and uncovered a new mechanism to regulate protein stability.
H3K4 三甲基化 (H3K4me3) 是由组蛋白甲基转移酶 Set1 催化的保守组蛋白修饰，其失调与病理学有关。在这里，我们表明 Set1 本质上是不稳定的，并阐明了其蛋白水平如何在细胞周期内和基因转录过程中受到控制。具体而言，Set1 包含一个破坏盒 (D-box)，该盒被 E3 连接酶 APC/C 识别，并通过泛素-蛋白酶体途径降解。Cla4 磷酸化 Set1 D-box 内的丝氨酸 228 (S228)，从而抑制 APC/C 介导的 Set1 蛋白水解。在基因转录过程中，PAF 复合物促进 Cla4 磷酸化 Set1-S228，并保护染色质结合的 Set1 免受降解。通过调节 Set1 的稳定性及其与染色质的结合，Cla4 和 APC/C 控制 H3K4me3 水平，从而调节基因转录、细胞周期进程和生物钟衰老。此外，有 141 种含有 D-box 的蛋白质可能被 Cla4 磷酸化，以防止它们被 APC/C 降解。我们解决了 Set1 稳定性如何受到控制的长期存在的问题，并揭示了一种新的调节蛋白质稳定性的机制。
