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Research Paper|Volume 9, Issue 9|pp 1957—1970

The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons

Jose F. Moruno-Manchon1, Edward C. Koellhoffer2, Jayakrishnan Gopakumar3, Shashank Hambarde4, Nayun Kim4,5, Louise D. McCullough2,5, Andrey S. Tsvetkov1,5,6
  • 1Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School at Houston, TX 77030, USA
  • 2Department of Neurology, the University of Texas McGovern Medical School at Houston, TX 77030, USA
  • 3Summer Research Program at the University of Texas McGovern Medical School at Houston, TX 77030, USA
  • 4Department of Microbiology and Molecular Genetics, the University of Texas McGovern Medical School at Houston, TX 77030, USA
  • 5The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
  • 6UTHealth Consortium on Aging, the University of Texas McGovern Medical School, Houston, TX 77030, USA
Received: May 18, 2017Accepted: August 25, 2017Published: September 12, 2017
https://doi.org/10.18632/aging.101282

Copyright: © 2017 Moruno-Manchon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double–strand breaks (DSBs) in cultured neurons. We also found that pyridostatin downregulated transcription of the Brca1 gene, a gene that is critical for DSB repair. Importantly, in an in vitro gel shift assay, we discovered that an antibody specific to the G-quadruplex structure binds to a synthetic oligonucleotide, which corresponds to the first putative G-quadruplex in the Brca1 gene promoter. Our results suggest that the G-quadruplex complexes regulate transcription in neurons. Studying the G-quadruplexes could represent a new avenue for neurodegeneration and brain aging research.