Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter.
Vandana, J Jeya
Chambers, Vicki S
Winnerdy, Fernaldo Richtia
Nucleic acids research
Oxford University Press
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Sengar, A., Vandana, J. J., Chambers, V. S., Di Antonio, M., Winnerdy, F. R., Balasubramanian, S., & Phan, A. T. (2019). Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter.. Nucleic acids research, 47 (3), 1564-1572. https://doi.org/10.1093/nar/gky1179
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 noncanonical G-quadruplex-forming sequence containing bulges within the PARP1 promoter. Structural features, like bulges, provide opportunities for selective chemical targeting of the non-canonical Gquadruplex 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.
Humans, Adenine, Guanine, DNA, Nuclear Magnetic Resonance, Biomolecular, DNA Repair, Nucleic Acid Conformation, G-Quadruplexes, Promoter Regions, Genetic, Poly (ADP-Ribose) Polymerase-1
Singapore National Research Foundation Investigatorship [NRF-NRFI2017-09]; Nanyang Technological University (NTU Singapore) (to A.T.P.); The Balasubramanian laboratory is core-funded by Cancer Research UK [C14303/A17197]; Cancer Research UK programme [C9681/A18618]; S.B. is a Welcome Trust Senior Investigator [099232/Z/12/Z]; The authors acknowledge the use of NMR facilities at the NTU Institute of Structural Biology. Funding for open access charge: Singapore National Research Foundation.
Cancer Research UK (18618)
Cancer Research UK (CB4330)
Wellcome Trust (099232/Z/12/Z)
External DOI: https://doi.org/10.1093/nar/gky1179
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287386
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/