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PANAD/C7orf25 interacts with NXF1 to promote CDK6 mRNA nuclear export and G1/S transition

ABSTRACT: Nuclear export factor 1 (NXF1) exerts mRNA transporter activity via binding to adaptors. We aimed to identify new NXF1 adaptors, and found that the R122/E125/G133/D139 amino acid residues of C7orf25 interacted with the Q20/K22/K23 residues in the RBD domain of NXF1, which disrupted the intramolecular interaction between the RBD and NTF2L domains of NXF1, consequently enhancing the binding of NXF1 to target mRNAs and promoting mRNA nuclear export. Furthermore, C7orf25 accelerated the G1/S transition and promoted tumor cell growth via interacting with NXF1 to promote nuclear export of CDK6 mRNA. The levels of C7orf25, NXF1, and CDK6 proteins were elevated in human hepatocellular carcinomas, and high C7orf25 levels were associated with worse survival. These findings identify C7orf25, which we named PANAD (Proliferation-Associated NXF1 Adaptor), as a novel NXF1-interacting adaptor and disclose the crucial roles of PANAD/C7orf25 in mRNA nuclear export and tumor growth, which provides potential target for cancer therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300612 | GEO | 2025/06/27

REPOSITORIES: GEO

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Project description:Through deep RNA-seq of human monocyte-derived macrophages, we identified RP11-184M15.1, a human macrophage-specific lincRNA, to be highly induced in the cytoplasm of IL-4-stimulated macrophage. Preliminary data showed that treatment of IL-4-stimulated THP1 human macrophages with RP11-184M15.1 small interfering RNA (siRNA) repressed apoptosis of resolving macrophages, as shown by decreased Annexin V+ macrophages, and reduced protein expression of cleaved PARP. Biotinylated RP11-184M15.1 pulldown coupled with mass spectrometry indicated an interaction between RP11-184M15.1 and zinc finger RNA-binding protein (ZFR). RIP corroborated the proposed interaction between RP11-184M15.1 and ZFR. RNAInter revealed mRNAs predicted to interact with ZFR, and some of those genes (e.g., ALYREF, CCNYL1) were also differentially expressed in RNA-seq data of control versus RP11-184M15.1 knockdown in IL-4-stimulated THP1 macrophages. qPCR validated that ALYREF and CCNYL1 expression are reduced with RP11-184M15.1 knockdown. In contrast, with ZFR siRNA, ALYREF and CCNYL1 mRNA expressions were elevated. Thus, a hypothesis to be further tested is that RP11-184M15.1 interacts with ZFR to regulate mRNA stability in IL-4-stimulated macrophages. Nuclear RNA export factor 1 (NXF1) was also validated by RIP to interact with RP11-184M15.1. NXF1 is a known interacting partner of ALYREF in the transcription-export (TREX) complex. With RP11-184M15.1 knockdown, the protein level of ALYREF decreased, and Ingenuity Pathway Analysis (IPA) of RNA-seq data of control versus RP11-184M15.1 knockdown revealed that THO complex subunit 5 homolog (THOC5), another component of the TREX complex, may be an upstream regulator. In addition, past studies have revealed that ALYREF and NXF1 are involved in nuclear export of inflammatory mRNAs and proinflammatory macrophage phenotype, respectively. With RP11-184M15.1 knockdown, there was decreased expression of inflammatory macrophage-associated genes. It may be possible that RP11-184M15.1 functions in mRNA export, along with NXF1 and ALYREF.

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PANAD/C7orf25 interacts with NXF1 to promote CDK6 mRNA nuclear export and G1/S transition

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