Recognition of intermolecular G‐quadruplexes by full length nucleophosmin. Effect of a leukaemia‐associated mutation

Bañuelos, Sonia; Lectez, Benoît; Taneva, Stefka G.; Ormaza, Georgina; Alonso-Mariño, Marián; Calle, Xabier; Urbaneja, Marı́a A.

doi:10.1016/j.febslet.2013.05.055

Cited by 22 publications

(11 citation statements)

References 22 publications

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“…It is possible that this could be alleviated by analyzing different domains of the enzyme, or using mutants that lack the ability to oligomerize. Nucleophosmin (NPM1) is an important protein able to bind G4s; the full‐length oligomeric NPM1 was previously shown to preferentially bind higher order G4 structures with μ m affinity using SPR assays, similar to that of its nucleic acid‐binding C‐terminal region of 70 residues . While the formation of higher order structures in vivo needs investigation, it is quite possible that the interaction of full‐length DNMT enzymes reported here is prevalent in higher order structures.…”

Section: Discussionmentioning

confidence: 93%

DNA G‐quadruplexes show strong interaction with DNA methyltransferases in vitro

et al. 2016

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The DNA methyltransferase enzymes (DNMTs) catalyzing cytosine methylation do so at specific locations of the genome, although with some level of redundancy. The de novo methyltransferases DNMT3A and 3B play a vital role in methylating the genome of the developing embryo in regions devoid of methylation marks. The ability of DNMTs to colocalize at sites of DNA damage is suggestive that recognition of mispaired bases and unusual structures is inherent to the function of these proteins. We provide evidence for G-quadruplex formation within imprinted gene promoters, and report highaffinity binding of recombinant human DNMTs to such DNA G-quadruplexes in vitro. These observations suggest a potential interaction of G-quadruplexes with the DNA methylation machinery, which may be of epigenetic and biological significance.

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Section: Discussionmentioning

confidence: 93%

DNA G‐quadruplexes show strong interaction with DNA methyltransferases in vitro

et al. 2016

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“…It has been shown that loss of these residues, crucial elements of the hydrophobic core of the C-terminal domain, impairs folding of the domain [ 11 ]. In turn, unfolding disrupts NPM nucleolar localization [ 11 ] due to inability to bind nucleic acids [ 17 , 31 ]. These findings are consistent with the described requirement of those two Trp residues for the nucleolar localization of the wild type protein [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

et al. 2015

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Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein, normally enriched in nucleoli, that performs several activities related to cell growth. NPM mutations are characteristic of a subtype of acute myeloid leukemia (AML), where mutant NPM seems to play an oncogenic role. AML-associated NPM mutants exhibit altered subcellular traffic, being aberrantly located in the cytoplasm of leukoblasts. Exacerbated export of AML variants of NPM is mediated by the nuclear export receptor CRM1, and due, in part, to a mutationally acquired novel nuclear export signal (NES). To gain insight on the molecular basis of NPM transport in physiological and pathological conditions, we have evaluated the export efficiency of NPM in cells, and present new data indicating that, in normal conditions, wild type NPM is weakly exported by CRM1. On the other hand, we have found that AML-associated NPM mutants efficiently form complexes with CRM1HA (a mutant CRM1 with higher affinity for NESs), and we have quantitatively analyzed CRM1HA interaction with the NES motifs of these mutants, using fluorescence anisotropy and isothermal titration calorimetry. We have observed that the affinity of CRM1HA for these NESs is similar, which may help to explain the transport properties of the mutants. We also describe NPM recognition by the import machinery. Our combined cellular and biophysical studies shed further light on the determinants of NPM traffic, and how it is dramatically altered by AML-related mutations.

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“…NPM1 was also shown to interact with G-quadruplex regions at oncogene promoters. Among them, the interaction of NPM1 with a G-quadruplex region present at the nuclease-hypersensitive element III of the c-MYC promoter was analyzed both with the isolated C-terminal domain (15,17) and in the context of the full-length protein (18). Similar dissociation constants were obtained in the two cases, confirming that the G-quadruplex binding activity is peculiar to the C-terminal domain.…”

Section: Nucleophosmin (Also Named B23 and Npm1mentioning

confidence: 56%

Synergic Role of Nucleophosmin Three-helix Bundle and a Flanking Unstructured Tail in the Interaction with G-quadruplex DNA

Arcovito

Chiarella

Longa

et al. 2014

Journal of Biological Chemistry

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Background: Nucleophosmin is a nucleolar protein that interacts with G-quadruplexes. Results: Site-directed mutagenesis and molecular dynamics unravel the role of single residues in complex formation. Conclusion: A disordered segment of nucleophosmin contributes to G-quadruplex recognition by facilitating the formation of an encounter complex and transiently interacting with the G-quadruplex. Significance: Understanding the role played by flanking fuzziness is an important issue in protein/DNA interactions.

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Recognition of intermolecular G‐quadruplexes by full length nucleophosmin. Effect of a leukaemia‐associated mutation

Cited by 22 publications

References 22 publications

DNA G‐quadruplexes show strong interaction with DNA methyltransferases in vitro

DNA G‐quadruplexes show strong interaction with DNA methyltransferases in vitro

Leukemia-Associated Mutations in Nucleophosmin Alter Recognition by CRM1: Molecular Basis of Aberrant Transport

Synergic Role of Nucleophosmin Three-helix Bundle and a Flanking Unstructured Tail in the Interaction with G-quadruplex DNA

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