| Autor: |
Moruno-Manchon JF; Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School at Houston, TX 77030, USA., Koellhoffer EC; Department of Neurology, the University of Texas McGovern Medical School at Houston, TX 77030, USA., Gopakumar J; Summer Research Program at the University of Texas McGovern Medical School at Houston, TX 77030, USA., Hambarde S; Department of Microbiology and Molecular Genetics, the University of Texas McGovern Medical School at Houston, TX 77030, USA., Kim N; Department of Microbiology and Molecular Genetics, the University of Texas McGovern Medical School at Houston, TX 77030, USA.; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA., McCullough LD; Department of Neurology, the University of Texas McGovern Medical School at Houston, TX 77030, USA.; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA., Tsvetkov AS; Department of Neurobiology and Anatomy, the University of Texas McGovern Medical School at Houston, TX 77030, USA.; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.; UTHealth Consortium on Aging, the University of Texas McGovern Medical School, Houston, TX 77030, USA. |
| Abstrakt: |
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. |
