TY - JOUR
T1 - The G-quadruplex DNA stabilizing drug pyridostatin promotes DNA damage and downregulates transcription of Brca1 in neurons
AU - Moruno-Manchon, Jose F.
AU - Koellhoffer, Edward C.
AU - Gopakumar, Jayakrishnan
AU - Hambarde, Shashank
AU - Kim, Nayun
AU - McCullough, Louise D.
AU - Tsvetkov, Andrey S.
N1 - Funding Information:
We thank members of the A.S.T. and L.D.M. laboratories for useful discussions. Raquel Cornell, Sharon Gordon, Summer Hensley, Diana Parker, and Martha Belmares provided administrative assistance. Many thanks to Dr. Redell for β-actin and GAPDH primers. This work was supported by he University of Texas McGovern Medical School at Houston, the Department of Neurobiology and Anatomy (A.S.T.), the GM116007 grant from the National Institutes of Health, and AU1875 from the Welch Foundation (N.K.).
Publisher Copyright:
© Moruno-Manchon et al.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
AB - 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.
KW - BRCA1
KW - DNA damage
KW - G-quadruplex
KW - Neurodegeneration
KW - Transcription
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U2 - 10.18632/aging.101282
DO - 10.18632/aging.101282
M3 - Article
C2 - 28904242
AN - SCOPUS:85030622968
VL - 9
SP - 1957
EP - 1970
JO - Aging
JF - Aging
SN - 0394-9532
IS - 9
ER -