2. Academic Validation
  3. The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons

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

  • Aging (Albany NY). 2017 Sep 12;9(9):1957-1970. doi: 10.18632/aging.101282.
Jose F Moruno-Manchon 1,  Edward C Koellhoffer 2,  Jayakrishnan Gopakumar 3,  Shashank Hambarde 4,  Nayun Kim 4 5,  Louise D McCullough 2 5,  Andrey S Tsvetkov 1 5 6
Affiliations

Affiliations

  • 1 Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School at Houston, TX 77030, USA.
  • 2 Department of Neurology, the University of Texas McGovern Medical School at Houston, TX 77030, USA.
  • 3 Summer Research Program at the University of Texas McGovern Medical School at Houston, TX 77030, USA.
  • 4 Department of Microbiology and Molecular Genetics, the University of Texas McGovern Medical School at Houston, TX 77030, USA.
  • 5 The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
  • 6 UTHealth Consortium on Aging, the University of Texas McGovern Medical School, Houston, TX 77030, USA.
PMID: 28904242 DOI: 10.18632/aging.101282
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.

Keywords

BRCA1; DNA damage; G-quadruplex; neurodegeneration; transcription.

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