Structure of Nucleophosmin DNA-binding Domain and Analysis of Its Complex with a G-quadruplex Sequence from the c-MYC Promoter

Gallo, Angelo; Sterzo, Claudio Lo; Mori, Mirko; Matteo, Adele Di; Bertini, Ivano; Banci, Lucia; Brunori, Maurizio; Federici, L.

doi:10.1074/jbc.m112.371013

Cited by 60 publications

(85 citation statements)

References 49 publications

(88 reference statements)

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“…4). 53 A similar behavior was observed in a number of other interactions, both protein-DNA and protein-protein, where flanking unstructured regions that do not physically interact with the binding partner in the final complex nevertheless contribute to define the binding energy. 54,55 Although the exact role played by this tail in nucleic acid recognition is currently under investigation, it has been recently shown that it significantly contributes to the thermal and chemical stability of the terminal three-helix bundle.…”

Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 63%

“…45 Lys257 and Lys267 were instead shown to be located at the interface with the c-MYC G-quadruplex. 53 This would suggest that acetylation events may interfere with NPM1 binding at rDNA regions and, indeed, it was shown that acetylated NPM1 loses nucleolar localization and roams in the nucleoplasm where it binds and possibly activates RNApolII. 65 The C-terminal domain is also subject of sumoylation at Lys230 and Lys263.…”

Section: Posttranslational Modifications and Molecules That Bind Npm1mentioning

confidence: 99%

“…45 Interestingly, this region was shown to be unstructured before and also after binding, and does not NMR data). 53 The Gquadruplex backbone is accommodated into a small positive groove formed by helices H1 and H2. Several interactions between lysine and asparagine residues and the DNA backbone phosphates stabilize the complex.…”

Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 99%

“…2(C) and 4]. 53 Even though this has to be experimentally proven, it may be hypothesized that Cys275 covalent linkage with this bulky alkaloid may interfere with G-quadruplex binding at nucleolar rDNA, thus releasing NPM1 from nucleoli. NPM1 dislocation would in turn lead to p53 stabilization through activation of the p14arf/HDM2 pathway.…”

Section: Posttranslational Modifications and Molecules That Bind Npm1mentioning

confidence: 99%

“…50 The structure of the NPM1 C-terminal extended domain in complex with the G-quadruplex oligonucleotide from the c-MYC promoter was recently investigated. 53 It was shown that a region comprised between helices H1 and H2 of the terminal three-helix bundle forms a small groove where a stretch of consecutive backbone phosphates of the main Gquadruplex scaffold is accommodated (Fig. 4).…”

Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 99%

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Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Federici

Falini

2013

Protein Science

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Nucleophosmin (NPM1) is an abundant, ubiquitously expressed protein mainly localized at nucleoli but continuously shuttling between nucleus and cytoplasm. NPM1 plays a role in several cellular functions, including ribosome biogenesis and export, centrosome duplication, chromatin remodeling, DNA repair, and response to stress stimuli. Much of the interest in this protein arises from its relevance in human malignancies. NPM1 is frequently overexpressed in solid tumors and is the target of several chromosomal translocations in hematologic neoplasms. Notably, NPM1 has been characterized as the most frequently mutated gene in acute myeloid leukemia (AML). Mutations alter the C-terminal DNAbinding domain of the protein and result in its aberrant nuclear export and stable cytosolic localization. In this review, we focus on the leukemia-associated NPM1 C-terminal domain and describe its structure, function, and the effect exerted by leukemic mutations. Finally, we discuss the possibility to target NPM1 for the treatment of cancer and, in particular, of AML patients with mutated NPM1 gene.

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Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 63%

Section: Posttranslational Modifications and Molecules That Bind Npm1mentioning

confidence: 99%

Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 99%

Section: Posttranslational Modifications and Molecules That Bind Npm1mentioning

confidence: 99%

Section: Npm1 As a G-quadruplex-binding Proteinmentioning

confidence: 99%

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Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Federici

Falini

2013

Protein Science

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Why to target G‐quadruplexes using peptides: Next‐generation G4‐interacting ligands

Sharma

Kundu

Kaur

et al. 2023

Journal of Peptide Science

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Guanine‐rich oligonucleotides existing in both DNA and RNA are able to fold into four‐stranded DNA secondary structures via Hoogsteen type hydrogen‐bonding, where four guanines self‐assemble into a square planar arrangement, which, when stacked upon each other, results in the formation of higher‐order structures called G‐quadruplexes. Their distribution is not random; they are more frequently present at telomeres, proto‐oncogenic promoters, introns, 5′‐ and 3′‐untranslated regions, stem cell markers, ribosome binding sites and so forth and are associated with various biological functions, all of which play a pivotal role in various incurable diseases like cancer and cellular ageing. Several studies have suggested that G‐quadruplexes could not regulate biological processes by themselves; instead, various proteins take part in this regulation and can be important therapeutic targets. There are certain limitations in using whole G4‐protein for therapeutics purpose because of its high manufacturing cost, laborious structure prediction, dynamic nature, unavailability for oral administration due to its degradation in the gut and inefficient penetration to reach the target site because of the large size. Hence, biologically active peptides can be the potential candidates for therapeutic intervention instead of the whole G4‐protein complex. In this review, we aimed to clarify the biological roles of G4s, how we can identify them throughout the genome via bioinformatics, the proteins interacting with G4s and how G4‐interacting peptide molecules may be the potential next‐generation ligands for targeting the G4 motifs located in biologically important regions.

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Quadruplex nucleic acids in KRAS targeted-cancer therapy

Xodo

2020

Annual Reports in Medicinal Chemistry

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Structure of Nucleophosmin DNA-binding Domain and Analysis of Its Complex with a G-quadruplex Sequence from the c-MYC Promoter

Cited by 60 publications

References 49 publications

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization

Why to target G‐quadruplexes using peptides: Next‐generation G4‐interacting ligands

Quadruplex nucleic acids in KRAS targeted-cancer therapy

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