两篇关于O-GlcNAc糖基化修饰的综述：

Targeting O-GlcNAcylation in cancer therapeutic resistance: The sugar Saga continues

Chen L, Hu M, Chen L, Peng Y, Zhang C, Wang X, Li X, Yao Y, Song Q, Li J, Pei H. 

Cancer Lett. 2024 Feb 23; 588: 216742.

    O-GlcNAc糖基化修饰调控多个关键的生物过程，在癌症耐药中发挥重要作用。O-GlcNAc修饰水平在多种癌症类型中显著升高，包括肺癌、乳腺癌、结直肠癌、胰腺癌、肝癌、胆管癌、食管癌、胃癌、膀胱癌、肾癌、前列腺癌、白血病、淋巴瘤、脑肿瘤、卵巢癌和宫颈癌。O-GlcNAc修饰水平的升高归因于几个因素，包括升高的葡萄糖、谷氨酰胺和脂肪酸等代谢物通过己糖胺生物合成途径（HBP）生成UDP-GlcNAc——O-GlcNAc修饰的供体底物，以及OGT/OGA酶的失调。这篇综述探讨了当前针对O-GlcNAc的研究工作和临床前研究，这些研究旨在通过调控O-GlcNAc修饰来克服肿瘤耐药。此外，文章还讨论了将O-GlcNAc糖基化作为癌症治疗靶点的潜在挑战和前景，特别强调了如何通过靶向O-GlcNAc修饰来提高治疗效果。作者还讨论了O-GlcNAc修饰作为癌症生物标志物的潜力，以及全局的O-GlcNAc修饰水平、OGT和OGA的表达水平和活性与癌症的疾病进展和治疗反应的相关性。

本综述提出了以下亟待解决的科学问题：

（1）O-GlcNAc糖基化修饰如何在时空上被调控？

（2）OGT在肿瘤发生发展中还有哪些底物？其生物学功能是什么？

（3）能否开发更多的化学生物学的工具？

（4）O-GlcNAc修饰与其他的翻译后修饰产生怎样的串扰？

（5）O-GlcNAc修饰在免疫系统与肿瘤微环境中有什么功能？

    摘要：O-连接的N-乙酰葡萄糖胺修饰（O-GlcNAcylation）是一种动态的翻译后修饰（PTM），在控制影响癌症进展和治疗抗性的多种细胞过程中具有深远的意义，包括细胞信号传导、代谢和表观遗传调控。从治疗的角度来看，O-GlcNAc调控药物外排、靶向和代谢。通过整合来自葡萄糖、脂质、氨基酸和核苷酸代谢途径的信号，O-GlcNAc充当营养传感器的角色，传递信号以影响基因组稳定性、上皮-间质转化（EMT）、细胞干性、细胞凋亡、自噬和细胞周期。O-GlcNAc还与肿瘤微环境（TME）和免疫反应密切相关。目前，靶向O-GlcNAc修饰的几种治疗策略主要处于临床前评估阶段，新开发的O-GlcNAc抑制剂显著提高了治疗效果。这篇综述中，作者系统概述了O-GlcNAc糖基化如何影响肿瘤耐药的机制，并探讨了未来癌症治疗中靶向O-GlcNAc修饰的前景和挑战。

    Abstract：O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a dynamic post-translational modification (PTM), holds profound implications in controlling various cellular processes such as cell signaling, metabolism, and epigenetic regulation that influence cancer progression and therapeutic resistance. From the therapeutic perspective, O-GlcNAc modulates drug efflux, targeting and metabolism. By integrating signals from glucose, lipid, amino acid, and nucleotide metabolic pathways, O-GlcNAc acts as a nutrient sensor and transmits signals to exerts its function on genome stability, epithelial-mesenchymal transition (EMT), cell stemness, cell apoptosis, autophagy, cell cycle. O-GlcNAc also attends to tumor microenvironment (TME) and the immune response. At present, several strategies aiming at targeting O-GlcNAcylation are under mostly preclinical evaluation, where the newly developed O-GlcNAcylation inhibitors markedly enhance therapeutic efficacy. Here we systematically outline the mechanisms through which O-GlcNAcylation influences therapy resistance and deliberate on the prospects and challenges associated with targeting O-GlcNAcylation in future cancer treatments.

OGT and OGA: Sweet Guardians of the Genome

Chen Wu,* , Jiaheng Li, Lingzi Lu, Mengyuan Li, Yanqiu Yuan*, Jing Li*. 

Journal of Biological Chemistry, 2024 . DOI: 10.1016/j.jbc.2024.107141

OGT和OGA可以被视为基因组的“甜蜜守护者”，本综述提出了以下亟待解决的科学问题：

（１）在同源重组修复(HR), 非同源末端连接(NHEJ), 碱基切除修复(BER),跨损伤合成(TLS)中，是否还有别的蛋白被糖基化?是否有糖基化蛋白参与其他的DNA 损伤修复通路,例如单链损伤修复(SSB)、断裂诱导修复(BIR)以及有丝分裂期的DNA合成通路(mitotic DNA synthesis; MiDAS)? 

（２）OGT与OGA如何感知DNA损伤而被招募到损伤位点? 这其中的机制是否是由于OGT/OGA上有特异的翻译后修饰? 还是由蛋白－蛋白相互作用介导? OGT/OGA与DNA结合后是否发生构象改变? 为什么OGA的招募比OGT有延迟?

（３）由于O-GlcNAc糖基化是响应营养信号的翻译后修饰，那么有没有可能DNA损伤修复通过O-GlcNAc修饰来响应不同的营养条件? O-GlcNAc在大脑和胰腺中丰度最高，那么O-GlcNAc修饰调控DNA损伤修复是否具有组织特异性?

    摘要：在过去的四十年中，人们付出了巨大努力来解读O-连接的N-乙酰葡萄糖胺修饰（O-GlcNAcylation）在众多生物过程中的作用。化学家和生物学家携手合作，共同探索这种独特、普遍但尚未被充分了解的翻译后修饰。最近，前沿的化学生物学和质谱工具的出现极大地促进了这一过程。与O-GlcNAc相比，DNA损伤应答（DDR）是一个相对深入研究的领域，其研究可以追溯到DNA结构阐明之前。出乎意料但又在情理之中的是，O-GlcNAc修饰能够调控多种DDR途径：同源重组（HR）、非同源末端连接（NHEJ）、碱基切除修复（BER）和跨损伤DNA合成（TLS）。在这篇综述中，作者首先回顾了O-GlcNAc转移酶（OGT）和O-GlcNAc水解酶（OGA）结构的最新研究，这对酶负责“书写”和“擦除”O-GlcNAc修饰。接着，作者详细阐述了OGT和OGA在DDR中的复杂作用。这只是我们全面理解O-GlcNAc如何调控生命蓝图——DNA的开始。

    Abstract：The past four decades have witnessed tremendous efforts in deciphering the role of O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in a plethora of biological processes. Chemists and biologists have joined hand in hand in the sweet adventure to unravel this unique, universal yet uncharted post-translation modification, and the recent advent of cutting-edge chemical biology and mass spectrometry tools has greatly facilitated the process. Compared to O-GlcNAc, DNA damage response (DDR) is a relatively intensively studied area that could be traced to before the elucidation of the structure of DNA. Unexpectedly, yet somewhat expectedly, O-GlcNAc has been found to regulate various DDR pathways: homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER) and translesion DNA synthesis (TLS). In this review, we first cover the recent structural studies of the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), the elegant duo that “writes” and “erases” O-GlcNAc modification. Then we delineate the intricate roles of OGT and OGA in DDR. We envision that this is only the beginning of our full appreciation of how O-GlcNAc regulates the blueprint of life-DNA.

参考文献：

1. Chen L, Hu M, Chen L, et al. Targeting O-GlcNAcylation in cancer therapeutic resistance: The sugar Saga continues[J]. Cancer Letters, 2024: 216742. https://doi.org/10.1016/j.canlet.2024.216742 

2. Wu C, Li J, Lu L, et al. OGT and OGA: Sweet Guardians of the Genome[J]. Journal of Biological Chemistry, 2024: 107141. https://doi.org/10.1016/j.jbc.2024.107141