Abstract
Poly (ADP-ribose) polymerase 1 (PARP1) has emerged as an attractive target for cancer therapy due to its key role in DNA repair processes. Inhibition of PARP1 in BRCA-mutated cancers has been observed to be clinically beneficial. Recent genome-mapping experiments have identified a non-canonical G-quadruplex-forming sequence containing bulges within the PARP1 promoter. Structural features, like bulges, provide opportunities for selective chemical targeting of the non-canonical G-quadruplex structure within the PARP1 promoter, which could serve as an alternative therapeutic approach for the regulation of PARP1 expression. Here we report the G-quadruplex structure formed by a 23-nucleotide G-rich sequence in the PARP1 promoter. Our study revealed a three-layered intramolecular (3+1) hybrid G-quadruplex scaffold, in which three strands are oriented in one direction and the fourth in the opposite direction. This structure exhibits unique structural features such as an adenine bulge and a G·G·T base triple capping structure formed between the central edgewise loop, propeller loop and 5′ flanking terminal. Given the highly important role of PARP1 in DNA repair and cancer intervention, this structure presents an attractive opportunity to explore the therapeutic potential of PARP1 inhibition via G-quadruplex DNA targeting.
Highlights
(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme known for its key role in the DNA repair processes [1]
Poly (ADP-ribose) polymerase-1 (PARP1) has been implicated in other cellular processes such as transcriptional regulation, chromatin remodelling, cell signaling and cell death [3,4,5]
We have revealed the (3+1) hybrid G-quadruplex folding topology adopted by the G-rich promoter sequence of the PARP1 gene
Summary
(ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme known for its key role in the DNA repair processes [1]. PARP1 binds to DNA breaks and recruits DNA repair proteins by catalyzing the formation of poly (ADP-ribose) scaffolds [1,2]. PARP1 has been implicated in other cellular processes such as transcriptional regulation, chromatin remodelling, cell signaling and cell death [3,4,5]. Synthetic lethality induced by PARP1 inhibition has emerged as a promising method for targeting tumor cells with defective homologous recombination pathways [6]. Inhibition of PARP1 activity in homologous recombination deficient cancer cells causes accumulation of unrepaired single-strand DNA breaks which are potentially converted to double-stranded DNA breaks, causing cell death selectively in those cancer cells [7]. Alternative strategies are required to selectively regulate PARP1 expression that can be used in combination with current PARP1 inhibitors or alone
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