Department of Biochemistry, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Department of Surgery, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
J Cell Sci. 2022 Jun 1;135(11). doi: 10.1242/jcs.259514. Epub 2022 Jun 8.
Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), an ubiquitin-like protein, is an essential regulator of the DNA damage response. Numerous studies have shown that neddylation (conjugation of NEDD8 to target proteins) dysfunction causes several human diseases, such as cancer. Hence clarifying the regulatory mechanism of neddylation could provide insight into the mechanism of genome stability underlying the DNA damage response (DDR) and carcinogenesis. Here, we demonstrate that dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a novel regulator of neddylation and maintains genome stability. Deletion of DYRK2 leads to persistent DNA double-strand breaks (DSBs) and subsequent genome instability. Mechanistically, DYRK2 promotes neddylation through forming a complex with NAE1, which is a component of NEDD8-activating enzyme E1, and maintaining its protein level by suppressing polyubiquitylation. The present study is the first to demonstrate that DYRK2 controls neddylation and is necessary for maintaining genome stability. This article has an associated First Person interview with the first author of the paper.
神经前体细胞表达的发育下调蛋白 8（NEDD8）是一种泛素样蛋白，是 DNA 损伤反应的必需调节剂。许多研究表明，NEDD8 连接酶（NEDD8 与靶蛋白的连接）功能障碍会导致多种人类疾病，如癌症。因此，阐明 NEDD8 连接酶的调控机制可以深入了解 DNA 损伤反应（DDR）和肿瘤发生的基因组稳定性机制。在这里，我们证明双特异性酪氨酸调节激酶 2（DYRK2）是 NEDD8 连接酶的新型调节剂，能够维持基因组稳定性。DYRK2 的缺失会导致持续的 DNA 双链断裂（DSBs）和随后的基因组不稳定性。在机制上，DYRK2 通过与 NAE1 形成复合物来促进 NEDD8 的连接，NAE1 是 NEDD8 激活酶 E1 的一个组成部分，并通过抑制多泛素化来维持其蛋白水平。本研究首次证明 DYRK2 控制 NEDD8 连接酶，并对维持基因组稳定性是必需的。本文还附有该论文第一作者的第一人称采访。
