Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length

Jonathan Dickerhoff, Buket Onel, Luying Chen, Yuwei Chen, Danzhou Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5′-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.

Original languageEnglish (US)
Pages (from-to)2533-2539
Number of pages7
JournalACS Omega
Volume4
Issue number2
DOIs
StatePublished - Feb 1 2019
Externally publishedYes

Fingerprint

Transcription
Proteins
Polymorphism
Genetic Promoter Regions
Gene expression
DNA
Cells
Nuclear magnetic resonance
Molecules
Pharmaceutical Preparations
nucleolin

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length. / Dickerhoff, Jonathan; Onel, Buket; Chen, Luying; Chen, Yuwei; Yang, Danzhou.

In: ACS Omega, Vol. 4, No. 2, 01.02.2019, p. 2533-2539.

Research output: Contribution to journalArticle

Dickerhoff, Jonathan ; Onel, Buket ; Chen, Luying ; Chen, Yuwei ; Yang, Danzhou. / Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length. In: ACS Omega. 2019 ; Vol. 4, No. 2. pp. 2533-2539.
@article{0d04f71bb52340a8a01213aa0e079e21,
title = "Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length",
abstract = "The important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5′-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.",
author = "Jonathan Dickerhoff and Buket Onel and Luying Chen and Yuwei Chen and Danzhou Yang",
year = "2019",
month = "2",
day = "1",
doi = "10.1021/acsomega.8b03580",
language = "English (US)",
volume = "4",
pages = "2533--2539",
journal = "ACS Omega",
issn = "2470-1343",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length

AU - Dickerhoff, Jonathan

AU - Onel, Buket

AU - Chen, Luying

AU - Chen, Yuwei

AU - Yang, Danzhou

PY - 2019/2/1

Y1 - 2019/2/1

N2 - The important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5′-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.

AB - The important MYC oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III1 motif. Formation of G4s suppresses MYC transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III1 motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind MYC G4 and repress MYC transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5′-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 MYC G4.

UR - http://www.scopus.com/inward/record.url?scp=85061099175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061099175&partnerID=8YFLogxK

U2 - 10.1021/acsomega.8b03580

DO - 10.1021/acsomega.8b03580

M3 - Article

AN - SCOPUS:85061099175

VL - 4

SP - 2533

EP - 2539

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 2

ER -