Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter.
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Authors
Sengar, Anjali
Vandana, J Jeya
Chambers, Vicki S
Winnerdy, Fernaldo Richtia
Publication Date
2019-02Journal Title
Nucleic acids research
ISSN
0305-1048
Publisher
Oxford University Press
Volume
47
Issue
3
Pages
1564-1572
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
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
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 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.
Keywords
Humans, Adenine, Guanine, DNA, Nuclear Magnetic Resonance, Biomolecular, DNA Repair, Nucleic Acid Conformation, G-Quadruplexes, Promoter Regions, Genetic, Poly (ADP-Ribose) Polymerase-1
Sponsorship
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.
Funder references
Cancer Research UK (18618)
Cancer Research UK (CB4330)
Wellcome Trust (099232/Z/12/Z)
Identifiers
External DOI: https://doi.org/10.1093/nar/gky1179
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287386