Making sense of G‐quadruplex and i‐motif functions in oncogene promoters

Brooks, Tracy A.; Kendrick, Samantha; Hurley, Laurence H.

doi:10.1111/j.1742-4658.2010.07759.x

Cited by 412 publications

(402 citation statements)

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“…Continued studies are worthy of detailed investigation, such as the long-term effects on telomerase, telomere and telomeric proteins essential for end-capping 50 , such as TRF2, POT1. As many other G-/C-rich regions in the human genome that can adopt i-motif/G-quadruplex structures, especially in the promoter regions of many genes and at recombination hotspots 8,36 , although SWNTs have relatively high specificity for telomeric DNA, they may also affect expressions of other genes, which are related to regulation of telomerase activity 8,46,51 . Therefore, telomerase inhibition may have involved mutiple cross-talks between them.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, i-motif has also been identified in some oncogene promoter regions, in concert with the G-quadruplex formation on the complementary strand 8 . Although significant progress has been made, because of i-motif structure instability and lack of specific i-motif binding agents, the biological effects of C-rich DNA to form i-motif structure have not been sufficiently clarified 2,7 .…”

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confidence: 99%

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Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

et al. 2012

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Both human telomeric G-rich and C-rich DnA have been considered as specific drug targets for cancer therapy. However, due to i-motif structure instability and lack of specific binding agents, it remains unclear whether stabilization of telomeric i-motif can inhibit telomerase activity. single-walled carbon nanotubes (sWnTs) have been reported as the first ligand that can selectively stabilize human telomeric i-motif DnA. Here we report that sWnTs can inhibit telomerase activity through stabilization of i-motif structure. The persistence of i-motif and the concomitant G-quadruplex eventually leads to telomere uncapping and displaces telomerebinding proteins from telomere. The dysfunctional telomere triggers DnA damage response and elicits upregulation of p16 and p21 proteins. This is the first example that sWnTs can inhibit telomerase activity and interfere with the telomere functions in cancer cells. These results provide new insights into understanding the biomedical effects of sWnTs and the biological importance of i-motif DnA.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

et al. 2012

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“…Affinity for other promoter G4 sequences, chosen to represent a variety of G4 structures including parallel, mixed, equilibrating, and tandem/more complex varieties (40), and doublestranded (ds) DNA complexes was measured using the competition dialysis assay (Fig. 2B).…”

Section: Validation Of Gqc-05 As a Myc G4 Binding Compoundmentioning

confidence: 99%

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Brown

Danford

Gokhale

et al. 2011

Journal of Biological Chemistry

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Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III 1 region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III 1 region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.The MYC proto-oncogene is a key component of normal cell growth and differentiation, with roles in a multitude of cellular processes. Normally, this gene is subject to tight transcriptional regulation; however, aberrant MYC expression is a common feature in an estimated 80% of all human malignancies (1-3); it is estimated that one-seventh of cancer deaths in the United States are associated with alterations in the MYC gene or its expression (4). Deregulation can arise through a variety of mechanisms (5-13), but most often MYC is activated through alterations in cell signaling that lead to increased transcription (14).Deregulated MYC can lead to transformation (15), often as an early step in the process of multistage cancer development, and one on which all other mutations are based (16,17). Cancer cells appear to be addicted to a deregulated MYC (18), which can be the "Achilles heel", offering the potential for a therapeutic window (19,20). The ability to selectively and potently down-regulate MYC would have considerable potential for both efficacy and safety in a variety of tumor types.There are several upstream elements within the MYC promoter that can potentially undergo strand separation to form either single-stranded or other non-B-DNA structures (21), which play a critical role in transcriptional control of MYC: the distant Far Upstream Element acts as a cruise control element, Z-DNA found both in the far upstream and the promoter regions, and a GC-rich region within the proximal promoter that acts as an on/off switch (22-28). This near upstream core promoter region, which is responsible for the initiation of 80 -90% of MYC transcription (29), contains the GC-rich nuclease hypersensitive element (NHE) 2 III 1 to which doublestranded (Sp1) and single-stranded (CNBP and hnRNP k) transcriptional factors bind. Within the MYC gene's NHE III 1 , a 31-base pair element consisting of five repeats of the sequence (C/T)C(C/T)TCCCCA serves as the "on/off switch" for MYC trans...

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“…The final adopted structure depends on several factors, including base sequence, strand orientation, loop connectivity and presence and type of cations. DNA strands in G-4 take anti-parallel, parallel, or hybrid conformations, and the nucleotide linkers between G-quartets can adopt a multitude of loop structures (2,3).…”

Section: Introductionmentioning

confidence: 99%

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

Nadai

Cimino‐Reale

Sattin

et al. 2014

International Journal of Oncology

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Abstract. naphthalene diimide (nDi) derivatives have shown high affinity for telomeric guanine (G)-quadruplexes and good antiproliferative activity in different human tumor experimental models. A trisubstituted compound (H-NDI-NMe 2 ) has been reported to stabilize the telomeric G-quadruplex and to cause telomere dysfunction and downregulation of telomerase expression. We further investigated its mechanism of action by analyzing the capability of the molecule to interfere with the expression levels of oncogenes, such as MYC, telome rase reverse transcriptase (TERT), KIT and BCL2, known to bear G-quadruplex-forming sequences within their promoters, in human tumor cell lines of different histological origin. Exposure to H-NDI-NMe 2 resulted in a cell type-dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H-NDI-NMe 2 bound with high affinity and effectively stabilized mainly MYC and BCL2, which share long sequences and the possibility of multiple G-quadruplex folding. The mRNA levels of both genes, but not protein amounts were affected by NDI treatment. Global gene expression analysis showed modulation of genes implicated in telomere function and mechanisms of cancer; however, G-quadruplex-mediated regulation of gene expression by H-NDI-NMe 2 was largely dependent on the cell context. These data indicate that a deeper knowledge on the molecular mechanisms and biological effects of G-quadruplex structures is still needed to help developing new effective anticancer agents.

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Making sense of G‐quadruplex and i‐motif functions in oncogene promoters

Cited by 412 publications

References 46 publications

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

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