Department of Oral and Maxillofacial Reconstruction, the Affiliated Hospital of Qingdao University, Qingdao 266555, China; School of Stomatology, Qingdao University, Qingdao 266003, China; Department of Oral and Maxillofacial Surgery, the Affiliated Hospital of Qingdao University, Qingdao 266555, China.
Department of Oral and Maxillofacial Surgery, Central Laboratory of Jinan Stamotological Hospital, Jinan Key Laboratory of Oral Tissue Regeneration, Jinan 250001, Shandong Province, China.
Int J Biol Macromol. 2024 Apr;264(Pt 1):130351. doi: 10.1016/j.ijbiomac.2024.130351. Epub 2024 Feb 24.
The DNA damage response (DDR) safeguards the stable genetic information inheritance by orchestrating a complex protein network in response to DNA damage. However, this mechanism can often hamper the effectiveness of radiotherapy and DNA-damaging chemotherapy in destroying tumor cells, causing cancer resistance. Inhibiting DDR can significantly improve tumor cell sensitivity to radiotherapy and DNA-damaging chemotherapy. Thus, DDR can be a potential target for cancer treatment. Post-translational modifications (PTMs) of DDR-associated proteins profoundly affect their activity and function by covalently attaching new functional groups. O-GlcNAcylation (O-linked-N-acetylglucosaminylation) is an emerging PTM associated with adding and removing O-linked N-acetylglucosamine to serine and threonine residues of proteins. It acts as a dual sensor for nutrients and stress in the cell and is sensitive to DNA damage. However, the explanation behind the specific role of O-GlcNAcylation in the DDR remains remains to be elucidated. To illustrate the complex relationship between O-GlcNAcylation and DDR, this review systematically describes the role of O-GlcNAcylation in DNA repair, cell cycle, and chromatin. We also discuss the defects of current strategies for targeting O-GlcNAcylation-regulated DDR in cancer therapy and suggest potential directions to address them.
DNA 损伤反应 (DDR) 通过协调复杂的蛋白质网络来应对 DNA 损伤，从而保护稳定的遗传信息遗传。然而，这种机制往往会阻碍放疗和 DNA 损伤化疗在破坏肿瘤细胞方面的有效性，导致癌症耐药。抑制 DDR 可以显著提高肿瘤细胞对放疗和 DNA 损伤化疗的敏感性。因此，DDR 可以成为癌症治疗的一个潜在靶点。DDR 相关蛋白的翻译后修饰 (PTMs) 通过共价连接新的功能基团，深刻影响其活性和功能。O-GlcNAcylation（O-链接-N-乙酰葡萄糖胺化）是一种新兴的 PTM，与将 O-链接 N-乙酰葡萄糖胺添加到蛋白质的丝氨酸和苏氨酸残基以及去除有关。它作为细胞中营养物质和应激的双重传感器，对 DNA 损伤敏感。然而，O-GlcNAcylation 在 DDR 中特定作用的具体解释仍有待阐明。为了说明 O-GlcNAcylation 与 DDR 之间的复杂关系，本综述系统描述了 O-GlcNAcylation 在 DNA 修复、细胞周期和染色质中的作用。我们还讨论了靶向 O-GlcNAcylation 调节的 DDR 在癌症治疗中当前策略的缺陷，并提出了潜在的解决方向。
