Discovery and Structural Characterization of G‑quadruplex DNA in Human Acetyl-CoA Carboxylase Gene Promoters: Its Role in Transcriptional Regulation and as a Therapeutic Target for Human Disease

Accumulating
evidence suggests that G-quadruplexes play vital roles
in gene expression, DNA replication, and recombination. Three distinct
promoters (PI, PII, and PIII) regulate human acetyl-CoA carboxylase
1 (ACC1) gene expression. In this study, we asked whether the G-rich
sequences within the human ACC1 (PI and PII) promoters can form G-quadruplex
structures and regulate normal DNA transactions. Using multiple complementary
methods, we show that G-rich sequences of PI and PII promoters form
intramolecular G-quadruplex structures and then establish unambiguously
the topologies of these structures. Importantly, G-quadruplex formation
in ACC1 gene promoter region blocks DNA replication and suppresses
transcription, and this effect was further augmented by G-quadruplex
stabilizing ligands. Altogether, these results are consistent with
the notion that G-quadruplex structures exist within the human ACC1
gene promoter region, whose activity can be suppressed by G-quadruplex
stabilizing ligands, thereby revealing a novel regulatory mechanism
of ACC1 gene expression and as a possible therapeutic target.