Posttranslational modifications of nuclear proteins, including transcription factors, nuclear receptors, and their coregulators, have attracted much attention in cancer research. Although phosphorylation of oligodendrocyte transcription factor 2 (Olig2) may contribute to the notorious resistance of gliomas to radiation and genotoxic drugs, the precise mechanisms remain elusive. We show here that in addition to phosphorylation, Olig2 is also conjugated by small ubiquitin-like modifier-1 (SUMO1) at three lysine residues K27, K76, and K112. SUMOylation is required for Olig2 to suppress p53-mediated cell cycle arrest and apoptosis induced by genotoxic damage, and to enhance resistance to temozolomide (TMZ) in glioma. Both SUMOylation and triple serine motif (TSM) phosphorylation of Olig2 are required for the antiapoptotic function. Olig2 SUMOylation enhances its genetic targeting ability, which in turn occludes p53 recruitment to Cdkn1a promoter for DNA-damage responses. Our work uncovers a SUMOylation-dependent regulatory mechanism of Olig2 in regulating cancer survival.

核蛋白的翻译后修饰，包括转录因子、核受体及其共调节因子，在癌症研究中引起了广泛关注。尽管少突胶质细胞转录因子 2 (Olig2) 的磷酸化可能导致神经胶质瘤对辐射和基因毒性药物的耐药性，但其确切机制仍然难以捉摸。我们在此展示，除了磷酸化外，Olig2 还与三个赖氨酸残基 K27、K76 和 K112 处的小泛素样修饰符 1 (SUMO1) 结合。Olig2 需要 SUMO 化来抑制由基因毒性损伤诱导的 p53 介导的细胞周期停滞和细胞凋亡，并增强胶质瘤对替莫唑胺 (TMZ) 的抗性。Olig2 的 SUMO 化和三重丝氨酸基序 (TSM) 磷酸化都是抗凋亡功能所必需的。用于 DNA 损伤反应的Cdkn1a启动子。我们的工作揭示了 Olig2 在调节癌症存活中的 SUMOylation 依赖性调节机制。