Solution equilibria of cytosine- and guanine-rich sequences near the promoter region of the n-myc gene that contain stable hairpins within lateral loops

Benabou, Sanae; Ferreira, Rubén; Aviñó, Anna; González, Carlos; Lyonnais, Sébastien; Solà, Marı́a; Eritja, Ramón; Jaumot, Joaquim; Gargallo, Raimundo

doi:10.1016/j.bbagen.2013.08.028

Cited by 41 publications

(61 citation statements)

References 46 publications

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“…[28] A:Tb ase pairs are not so common,b ut they have also been observed in monomeric [13,28,29] and tetrameric i-motifs. [30] In some cases, adenine protonation affects the structure [13,31] and the stability of the i-motif.…”

Section: Discussionmentioning

confidence: 92%

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

Garavís

Escaja

Gabelica

et al. 2015

Chemistry A European J

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International audience© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Human centromeric alpha-satellite DNA is composed of tandem arrays of two types of 171 bp monomers; type A and type B. The differences between these types are concentrated in a 17 bp region of the monomer called the A/B box. Here, we have determined the solution structure of the C-rich strand of the two main variants of the human alpha-satellite A box. We show that, under acidic conditions, the C-rich strands of two A boxes self-recognize and form a head-to-tail dimeric i-motif stabilized by four intercalated hemi-protonated C:C + base pairs. Interestingly, the stack of C:C + base pairs is capped by T:T and Hoogsteen A:T base pairs. The two main variants of the A box adopt a similar three-dimensional structure, although the residues involved in the formation of the i-motif core are different in each case. Together with previous studies showing that the B box (known as the CENP-B box) also forms dimeric i-motif structures, our finding of this non-canonical structure in the A box shows that centromeric alpha satellites in all human chromosomes are able to form i-motifs, which consequently raises the possibility that these structures may play a role in the structural organization of the centromere. Nucleosome organization: All human centromeric alpha-satellites contain sequences that can form dimeric i-motif structures in vitro (see figure). These regions occur every 171 bp and are found at the entrance and exit of the nucleosome. This finding suggests that the i-motif may play a role in the higher order nucleosome organization at the centromere. ; Peer Reviewe

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Section: Discussionmentioning

confidence: 92%

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

Garavís

Escaja

Gabelica

et al. 2015

Chemistry A European J

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“…As is the case for c-MYC , a G-quadruplex has been found close to the MYCN promoter region [190]. It has been suggested that the G-quadruplex at the c-MYC promoter could be involved in the positive control of MYC expression and that small molecules with high affinity for this structure could have the ability to inhibit the gene transcription [191].…”

Section: Mycn As a Therapeutic Targetmentioning

confidence: 99%

The MYCN Protein in Health and Disease

Ruiz-Pérez

Henley

Arsenian-Henriksson

2017

Genes

125

110

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MYCN is a member of the MYC family of proto-oncogenes. It encodes a transcription factor, MYCN, involved in the control of fundamental processes during embryonal development. The MYCN protein is situated downstream of several signaling pathways promoting cell growth, proliferation and metabolism of progenitor cells in different developing organs and tissues. Conversely, deregulated MYCN signaling supports the development of several different tumors, mainly with a childhood onset, including neuroblastoma, medulloblastoma, rhabdomyosarcoma and Wilms’ tumor, but it is also associated with some cancers occurring during adulthood such as prostate and lung cancer. In neuroblastoma, MYCN-amplification is the most consistent genetic aberration associated with poor prognosis and treatment failure. Targeting MYCN has been proposed as a therapeutic strategy for the treatment of these tumors and great efforts have allowed the development of direct and indirect MYCN inhibitors with potential clinical use.

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“…22,40 A number of i-motifs in the promoter element of various oncogenes have been characterized to date, including c-MYC , 41 BCL2 , 37 PDGFR-β , 38 VEGF , 42 RET, 43 Rb , 44 HRAS, 45 and n-myc . 46 In the case of the BCL2 i-motif, recent work has shown that this structure can be targeted with small molecules to differentially modulate gene expression. 26 This differential effect on gene expression depends on a dynamic equilibrium between the i-motif and a flexible hairpin, each of which can be independently targeted with steroid molecules.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of n-myc , both the i-motif and G-quadruplex formed in the promoter have a long lateral loop that is proposed to house a hairpin structure that contributes to the stability of the secondary structure. 46 Most recently it has been shown that it is possible to target both the G-quadruplex and the i-motif with different ligands to downregulate PDGFR- β gene expression. 38 Furthermore, in order to explain the effects of mutation on the G-quadruplexes in the G-rich strand, it is necessary to take into account the corresponding effects on the i-motifs in the C-rich strand.…”

Section: Introductionmentioning

confidence: 99%

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

et al. 2017

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Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex-interactive compound presents a new mechanism to modulate gene expression.

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Solution equilibria of cytosine- and guanine-rich sequences near the promoter region of the n-myc gene that contain stable hairpins within lateral loops

Cited by 41 publications

References 46 publications

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

Centromeric Alpha‐Satellite DNA Adopts Dimeric i‐Motif Structures Capped by AT Hoogsteen Base Pairs

The MYCN Protein in Health and Disease

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

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