作者: Liu, Shihan ; Xu, Zhu ; Xia, Anliang ; Yu, Yuanyuan ; Zhang, Jun ; Sun, Beicheng ; Tong, Junjie ; Xia, Jing ; Wang, Qiang ; Zhu, Wei-Guo ; An, Hongda ; Jiang, Yiyang ; Zhu, Mingming ; Geng, Longpo

AIMSRNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC).METHODSLaser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin.RESULTSNAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance.CONCLUSIONOur study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.

2025-06-01·Brain Research

Nuclear translocation of the LINE-1 encoded ORF1 protein alters nuclear envelope integrity in human neurons

Article

作者: Mailly, Philippe ; Joshi, Rajiv L ; Massiani-Beaudoin, Olivia ; Bonnifet, Tom ; Fuchs, Julia ; Znaidi, Rania ; Monnet, Héloïse

LINE-1 retrotransposons are increasingly implicated in aging and neurodegenerative diseases, yet the precise pathogenic mechanisms remain elusive. While the endonuclease and reverse transcriptase activities of LINE-1-encoded ORF2p can induce DNA damage and inflammation, a role of LINE-1 ORF1p in cellular dysfunctions stays unassigned. Here we demonstrate, using a neuronal cellular model, that ORF1p translocates into the nucleus upon arsenite-induced stress, directly interacting with nuclear import (KPNB1), nuclear pore complex (NUP153), and nuclear lamina (Lamin B1) proteins. Nuclear translocation of ORF1p disrupts nuclear integrity, nucleocytoplasmic transport, and heterochromatin structure, features linked to neurodegeneration and aging. Elevated nuclear ORF1p levels induced either by arsenite-induced stress, ORF1p overexpression, or as observed in Parkinson's disease post-mortem brain tissues correlate with impaired nuclear envelope (NE) morphology. Stress-induced nuclear alterations are mitigated by blocking ORF1p nuclear import or with the anti-aging drug remodelin. This study thus reveals a pathogenic action of nuclear ORF1p in human neurons driving NE alterations and thereby contributing to LINE-1-mediated cell toxicity.

2025-04-15·Proceedings of the National Academy of Sciences

Nat10-mediated N4-acetylcytidine modification enhances Nfatc1 translation to exacerbate osteoclastogenesis in postmenopausal osteoporosis

Article

作者: Xu, Bohan ; Meng, Keyu ; Ao, Xiang ; Zhang, Zhongmin ; Xiang, Xin ; Shang, Wanjing ; Zou, Peiqian ; Liu, Zhongyuan ; Ren, Zhengda ; Dai, Bingyang ; Luo, Li ; Li, Zehui ; Wang, Zhizhang ; Mo, Xiaoyi ; Xu, Jiajia ; Lan, Shanwei ; Lai, Zhongming ; Chen, Zesen

Increased differentiation or activity of osteoclasts is the key pathogenic factor of postmenopausal osteoporosis (PMOP). N4‐acetylcytidine (ac4C) modification, catalyzed by Nat10, is a novel posttranscriptional mRNA modification related to many diseases. However, its impact on regulating osteoclast activation in PMOP remains uncertain. Here, we initially observed that Nat10-mediated ac4C positively correlates with osteoclast differentiation of monocytes and low bone mass in PMOP. The specific knockout of Nat10 in monocytes and remodelin, a Nat10 inhibitor, alleviates ovariectomized (OVX)-induced bone loss by downregulating osteoclast differentiation. Mechanistically, epitranscriptomic analyses reveal that the nuclear factor of activated T cells cytoplasmic 1 (Nfatc1) is the key downstream target of ac4C modification during osteoclast differentiation. Subsequently, translatomic results demonstrate that Nat10-mediated ac4C enhances the translation efficiency (TE) of Nfatc1, thereby inducing Nfatc1 expression and consequent osteoclast maturation. Cumulatively, these findings reveal the promotive role of Nat10 in osteoclast differentiation and PMOP from a novel field of RNA modifications and suggest that Nat10 can be a target of epigenetic therapy for preventing bone loss in PMOP.

项与 Remodelin 相关的新闻（医药）

2023-05-25

·生物谷

华南大学衡阳医学院研究者综述了NA10为临床应用中诊断、治疗和预后的潜在靶点

到目前为止，已经发现了越来越多的RNA修饰，如N6甲基腺苷(M6A)、伪尿苷、5-甲基胞苷和N4-乙酰胞苷(Ac4C)，它们在mRNA的稳定、转录和翻译中是必不可少的，影响着多种细胞和生物过程。到目前为止，已经发现了越来越多的RNA修饰，如N6甲基腺苷(M6A)、伪尿苷、5-甲基胞苷和N4-乙酰胞苷(Ac4C)，它们在mRNA的稳定、转录和翻译中是必不可少的，影响着多种细胞和生物过程。 Ac4C是最近被发现的一种在mRNA稳定和翻译中具有重要作用的mRNA修饰，最初在细菌转移RNA(TRNA)反密码子中检测到，随后在真核丝氨酸和亮氨酸tRNAs和18S核糖体RNA(RRNA)中详细阐述。 Arango等人利用转录组的方法进行定位分析，发现ac4C主要富含在编码序列的50端(CDS)，少数分布在非翻译区(UTR)的30端。进一步的分析表明，ac4C通过acRIP-seq在摆动部位得到了强烈的富含，揭示了密码子的组成。图片来源: https://doi.org/10.1016/j.omtn.2023.03.023. 近日，来自华南大学衡阳医学院的研究者们在Molecular Therapy: Nucleic Acids杂志上发表了题为“Mechanisms of NAT10 as ac4C writer in diseases”的综述性文章，这篇综述将NA10确定为临床应用中诊断、治疗和预后的潜在靶点。早期，N4-乙酰胞苷(Ac4C)被认为是存在于tRNA和rRNA上的一种保守的核苷。最近的研究表明，ac4C也存在于人和酵母的mRNA中。N-乙酰转移酶样蛋白10(NAT10)是第一个在真核细胞RNA中发现的催化ac4C产生的酶，具有乙酰基转移酶活性和RNA结合活性。在本研究中，研究者首先描述了NAT10的结构和细胞定位。然后，我们总结了作为ac4C“编写者”的Nat10在mRNA稳定性和翻译效率、卵母细胞成熟、骨重建和脂肪酸代谢方面的积极作用。在疾病方面，研究者重点介绍了NAT10在多种肿瘤的增殖、转移和凋亡中的促进作用。还介绍了NAT10在系统性红斑狼疮中的免疫调节作用以及在甲型流感病毒中维持病毒RNA稳定和复制的作用。 NAT10与辅因子结合催化真核和原核细胞中的mRNA、tRNA和18S rRNA的ac4C修饰图片来源: https://doi.org/10.1016/j.omtn.2023.03.023 综上所述，研究者确定了NAT10在正常生理和发育过程中的生物学特性，在肿瘤的增殖、转移和凋亡中的促进作用，以及在其他非肿瘤疾病中的免疫调节、RNA稳定和复制调控作用。这些结果提供了新的见解，NA10作为一种有前景的疾病生物标志物，用于检测、进展和预后，以及通过改变ac4C改变而成为疾病治疗的潜在靶点。然而，还需要更多的临床数据来进一步证实Nat10的临床潜在价值。此外，到目前为止，除了Remodelin之外，很少有针对Nat10的抑制剂被报道。作为NA10抑制剂的有效和选择性化合物的开发具有较小的副作用，这可能是一个有趣和有意义的研究领域。（生物谷 Bioon.com）参考文献 Lihua Xie et al. Mechanisms of NAT10 as ac4C writer in diseases. Mol Ther Nucleic Acids. 2023 Apr 3;32:359-368. doi: 10.1016/j.omtn.2023.03.023.

信使RNA寡核苷酸

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