H4S47 O-GlcNAcylation regulates the activation of mammalian replication origins

Zou, Yingying; Pei, Jin; Long, Haizhen; Lan, Liting; Dong, Kaizhong; Wang, Tingting; Li, Ming Li; Zhao, Zhexuan; Zhu, L Q; Zhang, Gangxuan; Jin, Xin; Wang, Yan; Wen, Zengqi; Wei, Min; Feng, Yunpeng

doi:10.1038/s41594-023-00998-6

Cited by 8 publications

(1 citation statement)

References 72 publications

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“…Despite the growing recognition of the significant roles that protein-specific O-GlcNAcylation plays in various cellular processes and diseases, methods to uncover these roles remain underdeveloped. Genetic mutation of glycosites ,, can help elucidate the site-specific function of O-GlcNAcylation, but this approach has limitations: (1) it may alter protein folding and substrate recognition and interfere with other PTMs such as phosphorylation; (2) it lacks the necessary temporal and magnitude control due to the dynamic and substoichiometric nature of O-GlcNAcylation. Although nanobody-OGT and dual-specific RNA aptamers have been recently developed, their mechanisms inevitably constrain them from precise temporal and magnitude control.…”

Section: Discussionmentioning

confidence: 99%

Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules

Ma,

Khan,

et al. 2024

J. Am. Chem. Soc.

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Protein O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) plays a crucial role in regulating essential cellular processes. The disruption of the homeostasis of O-GlcNAcylation has been linked to various human diseases, including cancer, diabetes, and neurodegeneration. However, there are limited chemical tools for protein-and site-specific O-GlcNAc modification, rendering the precise study of the O-GlcNAcylation challenging. To address this, we have developed heterobifunctional small molecules, named O-GlcNAcylation TArgeting Chimeras (OGTACs), which enable protein-specific O-GlcNAcylation in living cells. OGTACs promote O-GlcNAcylation of proteins such as BRD4, CK2α, and EZH2 in cellulo by recruiting FKBP12 F36V -fused O-GlcNAc transferase (OGT), with temporal, magnitude, and reversible control. Overall, the OGTACs represent a promising approach for inducing protein-specific O-GlcNAcylation, thus enabling functional dissection and offering new directions for O-GlcNAc-targeting therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules

Ma,

Khan,

et al. 2024

J. Am. Chem. Soc.

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Poly (ADP-ribose) polymerase 1 promotes HuR/ELAVL1 cytoplasmic localization and inflammatory gene expression by regulating p38 MAPK activity

Fu,

Zhang,

Sun

et al. 2024

Cell. Mol. Life Sci.

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Post-transcriptional regulation of cytokine/chemokine mRNA turnover is critical for immune processes and contributes to the mammalian cellular response to diverse inflammatory stimuli. The ubiquitous RNA-binding protein human antigen R (HuR) is an integral regulator of inflammation-associated mRNA fate. HuR function is regulated by various post-translational modifications that alter its subcellular localization and ability to stabilize target mRNAs. Both poly (ADP-ribose) polymerase 1 (PARP1) and p38 mitogen-activated protein kinases (MAPKs) have been reported to regulate the biological function of HuR, but their specific regulatory and crosstalk mechanisms remain unclear. In this study, we show that PARP1 acts via p38 to synergistically promote cytoplasmic accumulation of HuR and stabilization of inflammation-associated mRNAs in cells under inflammatory conditions. Specifically, p38 binds to auto-poly ADP-ribosylated (PARylated) PARP1 resulting in the covalent PARylation of p38 by PARP1, thereby promoting the retention and activity of p38 in the nucleus. In addition, PARylation of HuR facilitates the phosphorylation of HuR at the serine 197 site mediated by p38, which then increases the translocation of HuR to the cytoplasm, ultimately stabilizing the inflammation-associated mRNA expression at the post-transcriptional level.

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