bims-nucpor 2021-11-07 papers

Issue of 2021–11–07
four papers selected by
Sara Mingu, Johannes Gutenberg University

PLoS Genet. 2021 Nov 01. 17(11): e1009889

A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription.

Amandine Bonnet, Carole Chaput, Noé Palmic, Benoit Palancade, Pascale Lesage.

Beyond their canonical function in nucleocytoplasmic exchanges, nuclear pore complexes (NPCs) regulate the expression of protein-coding genes. Here, we have implemented transcriptomic and molecular methods to specifically address the impact of the NPC on retroelements, which are present in multiple copies in genomes. We report a novel function for the Nup84 complex, a core NPC building block, in specifically restricting the transcription of LTR-retrotransposons in yeast. Nup84 complex-dependent repression impacts both Copia and Gypsy Ty LTR-retrotransposons, all over the S. cerevisiae genome. Mechanistically, the Nup84 complex restricts the transcription of Ty1, the most active yeast retrotransposon, through the tethering of the SUMO-deconjugating enzyme Ulp1 to NPCs. Strikingly, the modest accumulation of Ty1 RNAs caused by Nup84 complex loss-of-function is sufficient to trigger an important increase of Ty1 cDNA levels, resulting in massive Ty1 retrotransposition. Altogether, our study expands our understanding of the complex interactions between retrotransposons and the NPC, and highlights the importance for the cells to keep retrotransposon under tight transcriptional control.

DOI: https://doi.org/10.1371/journal.pgen.1009889

EMBO J. 2021 Nov 02. e108788

The nucleoporin Nup50 activates the Ran guanine nucleotide exchange factor RCC1 to promote NPC assembly at the end of mitosis.

Guillaume Holzer, Paola De Magistris, Cathrin Gramminger, Ruchika Sachdev, Adriana Magalska, Allana Schooley, Anja Scheufen, Birgitt Lennartz, Marianna Tatarek-Nossol, Hongqi Lue, Monika I Linder, Ulrike Kutay, Christian Preisinger, Daniel Moreno-Andres, Wolfram Antonin.

During mitotic exit, thousands of nuclear pore complexes (NPCs) assemble concomitant with the nuclear envelope to build a transport-competent nucleus. Here, we show that Nup50 plays a crucial role in NPC assembly independent of its well-established function in nuclear transport. RNAi-mediated downregulation in cells or immunodepletion of Nup50 protein in Xenopus egg extracts interferes with NPC assembly. We define a conserved central region of 46 residues in Nup50 that is crucial for Nup153 and MEL28/ELYS binding, and for NPC interaction. Surprisingly, neither NPC interaction nor binding of Nup50 to importin α/β, the GTPase Ran, or chromatin is crucial for its function in the assembly process. Instead, an N-terminal fragment of Nup50 can stimulate the Ran GTPase guanine nucleotide exchange factor RCC1 and NPC assembly, indicating that Nup50 acts via the Ran system in NPC reformation at the end of mitosis. In support of this conclusion, Nup50 mutants defective in RCC1 binding and stimulation cannot replace the wild-type protein in in vitro NPC assembly assays, whereas excess RCC1 can compensate the loss of Nup50.

Keywords: Nup50; RCC1; Xenopus egg extracts; mitotic exit; nuclear pore complex assembly

DOI: https://doi.org/10.15252/embj.2021108788

Front Cell Dev Biol. 2021 ;9 709923

Tpr Deficiency Disrupts Erythroid Maturation With Impaired Chromatin Condensation in Zebrafish Embryogenesis.

Shuang Wu, Kai Chen, Tao Xu, Ke Ma, Lei Gao, Cong Fu, Wenjuan Zhang, Changbin Jing, Chunguang Ren, Min Deng, Yi Chen, Yi Zhou, Weijun Pan, Xiaoe Jia.

Vertebrate erythropoiesis involves nuclear and chromatin condensation at the early stages of terminal differentiation, which is a unique process to distinguish mature erythrocytes from erythroblasts. However, the underlying mechanisms of chromatin condensation during erythrocyte maturation remain elusive. Here, we reported a novel zebrafish mutant cas7 with erythroid maturation deficiency. Positional cloning showed that a single base mutation in tprb gene, which encodes nucleoporin translocated promoter region (Tpr), is responsible for the disrupted erythroid maturation and upregulation of erythroid genes, including ae1-globin and be1-globin. Further investigation revealed that deficient erythropoiesis in tprb cas7 mutant was independent on HIF signaling pathway. The proportion of euchromatin was significantly increased, whereas the percentage of heterochromatin was markedly decreased in tprb cas7 mutant. In addition, TPR knockdown in human K562 cells also disrupted erythroid differentiation and dramatically elevated the expression of globin genes, which suggests that the functions of TPR in erythropoiesis are highly conserved in vertebrates. Taken together, this study revealed that Tpr played vital roles in chromatin condensation and gene regulation during erythroid maturation in vertebrates.

Keywords: Tpr; chromatin condensation; erythrocytes; erythroid maturation; zebrafish

DOI: https://doi.org/10.3389/fcell.2021.709923

Comput Biol Med. 2021 Oct 29. pii: S0010-4825(21)00749-6. [Epub ahead of print]139 104955

Oncogenic role of karyopherin α2 (KPNA2) in human tumors: A pan-cancer analysis.

Yiming Sun, Wenjing Li, Xiaolong Li, Hong Zheng, Yuan Qiu, Hua Yang.

BACKGROUND: KPNA2, a nuclear export protein that plays an important role in tumorigenesis, is an emerging hotspot target in oncology. Despite increasing supporting evidence of its importance, no pan-cancer analysis, across multiple databases, is available for in-depth data mining of the gene.
METHODS: Tumor data from both The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were explored to investigate the potential oncogenic roles of KPNA2. Diverse analytical methods were used to gain a full-scale understanding of KPNA2: gene expression, survival situations, genetic mutations, DNA methylation, sites of protein phosphorylation, immunocyte infiltration, and correlative cellular pathways.
RESULTS: KPNA2 is highly expressed in many cancers, and different correlations exist between KPNA2 expression and prognosis of cancer patients. cBioPortal reported that a nonsense mutation of R285* was considered to be the primary tumorigenic genetic alteration to KPNA2 and was found in cases of LUSC, STAD, and CESC. Enhanced phosphorylation of S62 was found in several cancers and the level of infiltration of cancer-associated fibroblasts was found to be linearly correlated with KPNA2 expression levels in ACC, BRCA, MESO, TGCT, THCA, and THYM. Correlations between KPNA2 DNA methylation and the pathogenesis of various tumors in TCGA were further identified. KEGG and GO enrichment analysis identified cell cycle, microtubule binding, and tubulin binding functions for KPNA2.
CONCLUSION: This is the first pan-cancer analysis focusing on KPNA2. It provides a comprehensive understanding about the role of KPNA2 in tumorigenesis and highlights the potential targeted role of KPNA2 for cancer study.

Keywords: KPNA2; Molecular mechanism; Pan-cancer analysis; Phosphorylation; Prognosis

DOI: https://doi.org/10.1016/j.compbiomed.2021.104955