The nuclear envelope (NE) serves as a major regulator of gene expression, by controlling the movement of mature RNA from the nucleus to the cytoplasm for translation. The NE is made up of a double mem brane. The outer nuclear membrane is continuous with the ER and has a composition distinct from that of the inner membrane. Nuclear pore complexes (NPCs) inserted within the NE regulate the trans port of molecules in and out of the nucleus.[1] Ions, small metabolites, and proteins smaller than 40 kDa passively diffuse across NPC channels. However, larger proteins and mRNAs are transported through NPCs via energy-dependent (guanosine triphosphate [GTP]) and signal-mediated processes that require chaperoning transport proteins. Approximately 3000 NPCs perforate the NE in animal cells. NPCs are approximately 120 nm in external diameter and composed of three major parts: (1) a central core containing a 10-nm channel, (2) a nuclear basket that can dilate in response to large cargoes, and (3) flexible fibrils that extend from the central core into the cytoplasm. NPCs contain approximately 50 different proteins (nucleoporins), arranged in a complex cylindrical structure with an octagonal symmetry.[2] Nucleoporins constitute the scaffold of the NPC and are arranged in rings. In the inner ring, nucleoporins containing repeats of two hydrophobic amino acids, phenylalanine and glycine (FG-repeats), are essential for the movement of the cargo-carrier complexes and for creating a selectivity barrier against the diffusion of nonnuclear proteins. The FG-nucleoporin filaments protrude toward the inner core of the NPC and the weak hydrophobic interactions between the FG-repeats and the cargo-carrier complexes mediate the passage of molecules.

One nucleoporin, Nup98, is involved in numerous translocations and resulting fusion proteins that cause MDS and leukemia. The N-terminal (Nt) domain that contains the FG-repeats is fused to more than 28 partners in MDS and AML and has shown leukemogenicity in cell lines and mouse models. Interestingly, it is likely Nup98’s transcriptional activation function rather than its role in nuclear pore formation that is critical in the function of these fusion proteins.[3]

Naked RNA cannot be exported through NPC channels. Rather, RNA export from the nucleus requires that newly synthesized RNAs undergo the previously described processing steps: 5′ capping, splicing, and 3′ polyadenylation. RNA-binding proteins, such as NXF1 that mediates the export of most mRNAs or XPO1, are required to fold and shuttle the modified RNA through NPCs. The eukaryotic translation initiation factor 4E (eIF4E) enhances nuclear export of a subset of RNA transcripts and is critical for proper granulocyte differentiation. Overexpression of eIF4E impedes myeloid maturation and can result in AML.[4] The cellular RNA export machinery is coopted by gammaretroviruses for the export of viral transcripts, such as binding of murine leukemia virus transcripts by the host cell’s NXF1.

References

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[1] Raices M, D’Angelo MA. Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat Rev Mol Cell Biol. 2012;13(11):687–699.

[2]  Hampoelz B, Andres-Pons A, Kastritis P, Beck M. Structure and assembly of the nuclear pore complex. Annu Rev Biophys. 2019;48:515–536.

[3]  Gough SM, Slape CI, Aplan PD. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood. 2011;118(24):6247–6257.

[4] Osborne MJ, Borden KLB. The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled. Immunol Rev. 2015;263(1):210–223.

مواضيع ذات صلة

RNA Heterogeneity

Regulation of RNA Processing: Capping, Splicing, and Polyadenylation

The Alpha Helix, Beta Sheet, and Beta Turn

Structures within Proteins

تصميم البوادئ primer design

كيف نعرف تسلسل الجين

Control of Gene Function and Biochemical Activity in Cells

آليات إصلاح الحمض النووي المتضرر DNA repair mechanisms

Hydrophobic Forces

Hydrogen Bonds and the Chelate Effect

Genes in the Cell Nucleus Control Protein Synthesis

RNA Proofreading