G-Quadruplex Modulation of SP1 Functional Binding Sites at the Proximal Promoter

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jan 5

PMID 33396937

Citations 19

Authors

Silvia Da Ros

Giulia Nicoletto

Riccardo Rigo

Silvia Ceschi

Eleonora Zorzan

Mauro Dacasto

Mery Giantin

Claudia Sissi

Affiliations

Soon will be listed here.

Abstract

The regulation of conformational arrangements of gene promoters is a physiological mechanism that has been associated with the fine control of gene expression. Indeed, it can drive the time and the location for the selective recruitment of proteins of the transcriptional machinery. Here, we address this issue at the proximal promoter where three G-quadruplex forming sites are present (kit1, kit2 and kit*). On this model, we focused on the interplay between G-quadruplex (G4) formation and SP1 recruitment. By site directed mutagenesis, we prepared a library of plasmids containing mutated sequences of the WT promoter that systematically exploited different G4 formation attitudes and SP1 binding properties. Our transfection data showed that the three different G4 sites of the promoter impact on SP1 binding and protein expression at different levels. Notably, kit2 and kit* structural features represent an on-off system for expression through the recruitment of transcription factors. The use of two G4 binders further helps to address kit2-kit* as a reliable target for pharmacological intervention.

Citing Articles

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G-quadruplexes as pivotal components of cis-regulatory elements in the human genome.

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Genetic variations in G-quadruplex forming sequences affect the transcription of human disease-related genes.

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References

Zorzan E, Da Ros S, Musetti C, Shahidian L, Coelho N, Bonsembiante F . Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models. Oncotarget. 2016; 7(16):21658-75. PMC: 5008313. DOI: 10.18632/oncotarget.7808. View

Liang J, Wu Y, Chen B, Zhang W, Tanaka Y, Sugiyama H . The C-kit receptor-mediated signal transduction and tumor-related diseases. Int J Biol Sci. 2013; 9(5):435-43. PMC: 3654492. DOI: 10.7150/ijbs.6087. View

Zorzan E, Elgendy R, Giantin M, Dacasto M, Sissi C . Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule. Sci Rep. 2018; 8(1):17107. PMC: 6244004. DOI: 10.1038/s41598-018-35516-y. View

Salsbury A, Dean T, Lemkul J . Polarizable Molecular Dynamics Simulations of Two Oncogene Promoter G-Quadruplexes: Effect of Primary and Secondary Structure on Loop and Ion Sampling. J Chem Theory Comput. 2020; 16(5):3430-3444. PMC: 7221321. DOI: 10.1021/acs.jctc.0c00191. View

Rigo R, Palumbo M, Sissi C . G-quadruplexes in human promoters: A challenge for therapeutic applications. Biochim Biophys Acta Gen Subj. 2016; 1861(5 Pt B):1399-1413. DOI: 10.1016/j.bbagen.2016.12.024. View

Francisco A, Paulo A . Oncogene Expression Modulation in Cancer Cell Lines by DNA G-Quadruplex-Interactive Small Molecules. Curr Med Chem. 2016; 24(42):4873-4904. DOI: 10.2174/0929867323666160829145055. View

Phan A, Patel D . Two-repeat human telomeric d(TAGGGTTAGGGT) sequence forms interconverting parallel and antiparallel G-quadruplexes in solution: distinct topologies, thermodynamic properties, and folding/unfolding kinetics. J Am Chem Soc. 2003; 125(49):15021-7. PMC: 4693644. DOI: 10.1021/ja037616j. View

Li X, Zheng K, Zhang J, Liu H, He Y, Yuan B . Guanine-vacancy-bearing G-quadruplexes responsive to guanine derivatives. Proc Natl Acad Sci U S A. 2015; 112(47):14581-6. PMC: 4664295. DOI: 10.1073/pnas.1516925112. View

Wei D, Husby J, Neidle S . Flexibility and structural conservation in a c-KIT G-quadruplex. Nucleic Acids Res. 2014; 43(1):629-44. PMC: 4288176. DOI: 10.1093/nar/gku1282. View

10.

Park G, Plummer 3rd H, Krystal G . Selective Sp1 binding is critical for maximal activity of the human c-kit promoter. Blood. 1998; 92(11):4138-49. View

11.

Ducani C, Bernardinelli G, Hogberg B, Keppler B, Terenzi A . Interplay of Three G-Quadruplex Units in the KIT Promoter. J Am Chem Soc. 2019; 141(26):10205-10213. DOI: 10.1021/jacs.8b12753. View

12.

Ashman L, Griffith R . Therapeutic targeting of c-KIT in cancer. Expert Opin Investig Drugs. 2012; 22(1):103-15. DOI: 10.1517/13543784.2013.740010. View

13.

Fleming A, Zhou J, Wallace S, Burrows C . A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These "Spare Tires" Have an Evolved Function?. ACS Cent Sci. 2015; 1(5):226-233. PMC: 4571166. DOI: 10.1021/acscentsci.5b00202. View

14.

Pittoni P, Piconese S, Tripodo C, Colombo M . Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors. Oncogene. 2010; 30(7):757-69. DOI: 10.1038/onc.2010.494. View

15.

Davis J, Spada G . Supramolecular architectures generated by self-assembly of guanosine derivatives. Chem Soc Rev. 2007; 36(2):296-313. DOI: 10.1039/b600282j. View

16.

Folini M, Pivetta C, Zagotto G, De Marco C, Palumbo M, Zaffaroni N . Remarkable interference with telomeric function by a G-quadruplex selective bisantrene regioisomer. Biochem Pharmacol. 2010; 79(12):1781-90. DOI: 10.1016/j.bcp.2010.02.018. View

17.

Zagotto G, Ricci A, Vasquez E, Sandoli A, Benedetti S, Palumbo M . Tuning G-quadruplex vs double-stranded DNA recognition in regioisomeric lysyl-peptidyl-anthraquinone conjugates. Bioconjug Chem. 2011; 22(10):2126-35. DOI: 10.1021/bc200389w. View

18.

Rigo R, Dean W, Gray R, Chaires J, Sissi C . Conformational profiling of a G-rich sequence within the c-KIT promoter. Nucleic Acids Res. 2017; 45(22):13056-13067. PMC: 5727440. DOI: 10.1093/nar/gkx983. View

19.

Raiber E, Kranaster R, Lam E, Nikan M, Balasubramanian S . A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro. Nucleic Acids Res. 2011; 40(4):1499-508. PMC: 3287196. DOI: 10.1093/nar/gkr882. View

20.

Hsu S, Varnai P, Bugaut A, Reszka A, Neidle S, Balasubramanian S . A G-rich sequence within the c-kit oncogene promoter forms a parallel G-quadruplex having asymmetric G-tetrad dynamics. J Am Chem Soc. 2009; 131(37):13399-409. PMC: 3055164. DOI: 10.1021/ja904007p. View