Dataset Information

Nuclear polysaccharides maintain H3K9me3-heterochromatin and genomic stability

ABSTRACT: Polysaccharides are traditionally confined to the cell surface and extracellular space, whereas their nuclear roles remain unclear. Here, we show that N-glycans are present in the nucleus and modify inner nuclear membrane (INM) proteins across multiple cell types. Disruption of INM protein N-glycosylation reduces H3K9me3 in lamina-associated domains and induces genomic instability by impairing SETDB1 association with the INM. Notably, canonical ER N-glycan biosynthetic machinery contributes to INM protein N-glycosylation. Our findings reveal a previously unrecognized nuclear function of polysaccharides.

ORGANISM(S): Mus Musculus

SUBMITTER: Shisheng Sun

PROVIDER: PXD072505 | iProX | Tue Dec 30 00:00:00 GMT 2025

REPOSITORIES: iProX

ACCESS DATA

Publications

Nuclear N-glycosylation maintains H3K9me3 heterochromatin and genomic stability.

Tang Xiuxiao X Dai Ranran R Qing Li L Zhang Zhida Z Li Hongmei H Lu Lizi L Lin Hancheng H Ji Danling D Dan Wei W He Yuqi Y Liu Xinyi X Yang Tao T Chang Wakam W Mao Yang Y Sun Shisheng S Ding Junjun J

Nature cell biology 20260428 6

Polysaccharides are known to be synthesized by enzymes in the endoplasmic reticulum and Golgi apparatus and transported through the secretory pathway to the cell surface or extracellular space, where they mediate essential biological processes. While classical localization and functions of polysaccharides are well established, their presence and potential roles in the nucleus remain unclear. Here we demonstrate that N-glycans, a type of polysaccharides, modify inner nuclear membrane (INM) protei ...[more]

PMID: 42050147

Similar Datasets

Project description:Although hepatitis B virus (HBV) has been established to cause hepatocellular carcinoma (HCC), the exact mechanism remains to be clarified. Type II ground glass hepatocytes (GGH) harboring the HBV pre-S2 mutant large surface protein have been recognized as morphologically distinct hallmark of HCC in advanced stages of chronic HBV infection. Considering its pre-neoplastic nature, we hypothesized that type II GGH may exhibit high genomic instability, which is important for the carcinogenic process in chronic HBV carriers. In this study we found that pre-S2 mutant LHBS directly interacted with importin 1, the key factor that recognizes cargos undergoing nuclear transportation mediated by the importin 1 associated nuclear pore complex (NPC). By interacting with importin 1, which inhibits its function as an NPC factor, pre-S2 mutant LHBS blocked nuclear transportation of an essential DNA repair and recombination factor Nijmegen breakage syndrome 1 (NBS1) upon DNA damage, thereby delaying formation of nuclear foci at the sites of DNA double strand breaks. Pre-S2 mutant LHBS was also found to block NBS1-mediated homologous recombination repair and induce multi-nucleation of cells. In addition, pre-S2 mutant LHBS transgenic mice showed genomic instability indicated by increased global gene copy number variations (CNV), which were significantly higher than those in hepatitis B virus X mice, indicating that pre-S2 mutant LHBS is the major viral oncoprotein inducing genomic instability in HBV-infected hepatocytes. Consistently, the human type II GGHs in HCC patients exhibited increased DNA double-strand breaks representing significant genomic instability. In conclusion, type II GGH harboring HBV pre-S2 mutant oncoprotein represents a high-risk marker for the loss of genome integrity in chronic HBV carriers and explains the complex chromosome changes in HCCs. Non-tumorous liver sections from four each the HBx and pre-S2 mutant LHBS transgenic mice and 3 double transgenic mice between 9 and 22 months old were examined for gene gain and loss.

Project description:Colorectal cancer, one of the most frequent types of malignancy in the Western world, develops through a multi-step process. The main pathways establishing transformation of normal mucosa to invasive carcinoma include chromosomal instability (CIN), microsatellite instability (MSI) or epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological and genetic characteristics. In general, altered cell surface glycosylation has been linked to colorectal cancer progression, however the impact of MSI-specific pathways on the glycosylation machinery of MSI colon cancer cells has not been investigated yet. In a recent study (Patsos et al., 2009) we have shown that MSI-specific mutations induce marked alterations in cell surface glycosylation, indicating specific changes in the expression of glyco-genes. Therefore the purpose of our experiment is to define these changes by glyco-gene chip analysis. Biallelic mutational inactivation of MSI target genes is believed to drive MSI tumorigenesis. TGFBR2, ACVR2 and AIM2 are among the most frequently mutated genes in MSI colorectal adenomas and carcinomas and functional studies indicate their contribution to MSI-carcinogenesis. A first general screening approach by lectin FACS analysis indicated a correlation between functional inactivation of these genes and cell surface glycosylation of the MSI colon cell line HCT116 (Patsos et al., 2009). For detailed analysis of the altered glycosylation pattern and the underlying molecular mechanisms we have established HCT116 double stable transfectants that allow doxycycline-inducible expression of the three MSI target genes TGFBR2, ACVR2 and AIM2 in a reversible manner. Thus we can experimentally control the expression of the MSI-genes and analyze short and long-term effects on different cell functions, including glycosylation. From the application of the glyco-gene chip for analysis of the transfectants we expect to gain seminal information on the influence of MSI-target genes on glycan expression and function in MSI tumor cells. Correlating loss-of-function of MSI target genes not yet linked with glycosylation to the regulation of the glycophenotype is a novel approach to investigate the glycobiology of tumor cells. In addition it is also suitable to detect new MSI-(glyco)markers for clinical applications, including diagnostic tumor markers and specific targets for immunotherapies.

Dataset Information

Nuclear polysaccharides maintain H3K9me3-heterochromatin and genomic stability

Publications

Nuclear N-glycosylation maintains H3K9me3 heterochromatin and genomic stability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets