bims-nucpor 2024-06-30 papers

Issue of 2024–06–30
four papers selected by
Sara Mingu, Johannes Gutenberg University

Nucleus. 2024 Dec;15(1): 2373052

Pre-ribosomal particles from nucleoli to cytoplasm.

Ulrich Kubitscheck, Jan Peter Siebrasse.

The analysis of nucleocytoplasmic transport of proteins and messenger RNA has been the focus of advanced microscopic approaches. Recently, it has been possible to identify and visualize individual pre-ribosomal particles on their way through the nuclear pore complex using both electron and light microscopy. In this review, we focused on the transport of pre-ribosomal particles in the nucleus on their way to and through the pores.

Keywords: Electron tomography; RNA export; fluorescence microscopy; intranuclear mobility; localization precision; nucleocytoplasmic transport; single particle tracking

DOI: https://doi.org/10.1080/19491034.2024.2373052

Nucleic Acids Res. 2024 Jun 25. pii: gkae526. [Epub ahead of print]

SUMO protease and proteasome recruitment at the nuclear periphery differently affect replication dynamics at arrested forks.

Kamila Schirmeisen, Karel Naiman, Karine Fréon, Laetitia Besse, Shrena Chakraborty, Anissia Ait Saada, Antony M Carr, Karol Kramarz, Sarah A E Lambert.

Nuclear pore complexes (NPCs) have emerged as genome organizers, defining a particular nuclear compartment enriched for SUMO protease and proteasome activities, and act as docking sites for the repair of DNA damage. In fission yeast, the anchorage of perturbed replication forks to NPCs is an integral part of the recombination-dependent replication restart mechanism (RDR) that resumes DNA synthesis at terminally dysfunctional forks. By mapping DNA polymerase usage, we report that SUMO protease Ulp1-associated NPCs ensure efficient initiation of restarted DNA synthesis, whereas proteasome-associated NPCs sustain the progression of restarted DNA polymerase. In contrast to Ulp1-dependent events, this last function is not alleviated by preventing SUMO chain formation. By analyzing the role of the nuclear basket, the nucleoplasmic extension of the NPC, we reveal that the activities of Ulp1 and the proteasome cannot compensate for each other and affect the dynamics of RDR in distinct ways. Our work probes two distinct mechanisms by which the NPC environment ensures optimal RDR, both controlled by different NPC components.

DOI: https://doi.org/10.1093/nar/gkae526

EMBO J. 2024 Jun 25.

Physiological regulation of neuronal Wnt activity is essential for TDP-43 localization and function.

Nan Zhang, Anna Westerhaus, Macey Wilson, Ethan Wang, Loyal Goff, Shanthini Sockanathan.

Nuclear exclusion of the RNA- and DNA-binding protein TDP-43 can induce neurodegeneration in different diseases. Diverse processes have been implicated to influence TDP-43 mislocalization, including disrupted nucleocytoplasmic transport (NCT); however, the physiological pathways that normally ensure TDP-43 nuclear localization are unclear. The six-transmembrane enzyme glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Here we show that GDE2 maintains TDP-43 nuclear localization by regulating the dynamics of canonical Wnt signaling. Ablation of GDE2 causes aberrantly sustained Wnt activation in adult neurons, which is sufficient to cause NCT deficits, nuclear pore abnormalities, and TDP-43 nuclear exclusion. Disruption of GDE2 coincides with TDP-43 abnormalities in postmortem tissue from patients with amyotrophic lateral sclerosis (ALS). Further, GDE2 deficits are evident in human neural cell models of ALS, which display erroneous Wnt activation that, when inhibited, increases mRNA levels of genes regulated by TDP-43. Our study identifies GDE2 as a critical physiological regulator of Wnt signaling in adult neurons and highlights Wnt pathway activation as an unappreciated mechanism contributing to nucleocytoplasmic transport and TDP-43 abnormalities in disease.

Keywords: GDE2; Neurodegeneration; Nucleocytoplasmic Transport; TDP-43; WNT

DOI: https://doi.org/10.1038/s44318-024-00156-8

Cancer Med. 2024 Jul;13(13): e7445

NUP98-BPTF promotes oncogenic transformation through PIM1 upregulation.

Mina Noura, Sakura Tomita, Takahiko Yasuda, Shinobu Tsuzuki, Hitoshi Kiyoi, Fumihiko Hayakawa.

INTRODUCTION: Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown.
MATERIALS AND METHODS: To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells.
RESULTS: NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD).
CONCLUSION: We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.

Keywords: NUP98‐BPTF; PIM1; RNA‐seq; cell transformation; leukemia

DOI: https://doi.org/10.1002/cam4.7445