Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence Within the PARP1 Gene Promoter Region

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 Jul 28

PMID 35897968

Authors

Stefania Mazzini

Salvatore Princiotto

Roberto Artali

Loana Musso

Anna Avino

Ramon Eritja

Raimundo Gargallo

Sabrina Dallavalle

Affiliations

Soon will be listed here.

Abstract

The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.

Citing Articles

Insights into the Molecular Structure, Stability, and Biological Significance of Non-Canonical DNA Forms, with a Focus on G-Quadruplexes and i-Motifs.

Obara P, Wolski P, Panczyk T Molecules. 2024; 29(19).

PMID: 39407611 PMC: 11477922. DOI: 10.3390/molecules29194683.

References

Sanner M . Python: a programming language for software integration and development. J Mol Graph Model. 2000; 17(1):57-61. View

Murai J, Huang S, Das B, Renaud A, Zhang Y, Doroshow J . Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012; 72(21):5588-99. PMC: 3528345. DOI: 10.1158/0008-5472.CAN-12-2753. View

Dallavalle S, Musso L, Artali R, Avino A, Scaglioni L, Eritja R . G-quadruplex binding properties of a potent PARP-1 inhibitor derived from 7-azaindole-1-carboxamide. Sci Rep. 2021; 11(1):3869. PMC: 7887208. DOI: 10.1038/s41598-021-83474-9. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Morales J, Li L, Fattah F, Dong Y, Bey E, Patel M . Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr. 2014; 24(1):15-28. PMC: 4806654. DOI: 10.1615/critreveukaryotgeneexpr.2013006875. View

Musso L, Mazzini S, Rossini A, Castagnoli L, Scaglioni L, Artali R . c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach. Biochim Biophys Acta Gen Subj. 2017; 1862(3):615-629. DOI: 10.1016/j.bbagen.2017.12.002. View

Dallavalle S, Princiotto S, Mattio L, Artali R, Musso L, Avino A . Investigation of the Complexes Formed between PARP1 Inhibitors and PARP1 G-Quadruplex at the Gene Promoter Region. Int J Mol Sci. 2021; 22(16). PMC: 8395737. DOI: 10.3390/ijms22168737. View

Lagah S, Tan I, Radhakrishnan P, Hirst R, Ward J, OCallaghan C . RHPS4 G-quadruplex ligand induces anti-proliferative effects in brain tumor cells. PLoS One. 2014; 9(1):e86187. PMC: 3893285. DOI: 10.1371/journal.pone.0086187. View

Sengar A, Vandana J, Chambers V, Di Antonio M, Winnerdy F, Balasubramanian S . Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter. Nucleic Acids Res. 2018; 47(3):1564-1572. PMC: 6379715. DOI: 10.1093/nar/gky1179. View

10.

Kantidze O, Luzhin A, Nizovtseva E, Safina A, Valieva M, Golov A . The anti-cancer drugs curaxins target spatial genome organization. Nat Commun. 2019; 10(1):1441. PMC: 6441033. DOI: 10.1038/s41467-019-09500-7. View

11.

Murai J, Huang S, Renaud A, Zhang Y, Ji J, Takeda S . Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol Cancer Ther. 2013; 13(2):433-43. PMC: 3946062. DOI: 10.1158/1535-7163.MCT-13-0803. View

12.

Gargallo R . Hard/soft hybrid modeling of temperature-induced unfolding processes involving G-quadruplex and i-motif nucleic acid structures. Anal Biochem. 2014; 466:4-15. DOI: 10.1016/j.ab.2014.08.008. View

13.

Gavathiotis E, Searle M . Structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat: evidence for A-tetrad formation from NMR and molecular dynamics simulations. Org Biomol Chem. 2003; 1(10):1650-6. DOI: 10.1039/b300845m. View

14.

Ashworth A . A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008; 26(22):3785-90. DOI: 10.1200/JCO.2008.16.0812. View

15.

Pazzaglia S, Pioli C . Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases. Cells. 2019; 9(1). PMC: 7017201. DOI: 10.3390/cells9010041. View

16.

Galindo-Murillo R, Robertson J, Zgarbova M, Sponer J, Otyepka M, Jurecka P . Assessing the Current State of Amber Force Field Modifications for DNA. J Chem Theory Comput. 2016; 12(8):4114-27. PMC: 4980684. DOI: 10.1021/acs.jctc.6b00186. View

17.

de la Hoz A, Navarro A, Avino A, Eritja R, Gargallo R . Studies on the interactions of Ag(i) with DNA and their implication on the DNA-templated synthesis of silver nanoclusters and on the interaction with complementary DNA and RNA sequences. RSC Adv. 2022; 11(15):9029-9042. PMC: 8695332. DOI: 10.1039/d1ra00194a. View

18.

Kraus W . Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Curr Opin Cell Biol. 2008; 20(3):294-302. PMC: 2518631. DOI: 10.1016/j.ceb.2008.03.006. View

19.

Maizels N, Gray L . The G4 genome. PLoS Genet. 2013; 9(4):e1003468. PMC: 3630100. DOI: 10.1371/journal.pgen.1003468. View

20.

Santos T, Salgado G, Cabrita E, Cruz C . G-Quadruplexes and Their Ligands: Biophysical Methods to Unravel G-Quadruplex/Ligand Interactions. Pharmaceuticals (Basel). 2021; 14(8). PMC: 8401999. DOI: 10.3390/ph14080769. View