Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter

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-qu...

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Main Authors: Chambers, Vicki S., Di Antonio, Marco, Sengar, Anjali, Balasubramanian, Shankar, Phan, Anh Tuân, Winnerdy, Fernaldo Richtia, Vandana, J. Jeya
Other Authors: School of Physical and Mathematical Sciences
Format: Article
Language:English
Published: 2019
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Online Access:https://hdl.handle.net/10356/86025
http://hdl.handle.net/10220/49248
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-860252023-02-28T19:34:01Z Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter Chambers, Vicki S. Di Antonio, Marco Sengar, Anjali Balasubramanian, Shankar Phan, Anh Tuân Winnerdy, Fernaldo Richtia Vandana, J. Jeya School of Physical and Mathematical Sciences G-quadruplex PARP1 Promoter Science::Chemistry 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. NRF (Natl Research Foundation, S’pore) Published version 2019-07-10T04:40:09Z 2019-12-06T16:14:36Z 2019-07-10T04:40:09Z 2019-12-06T16:14:36Z 2018 Journal Article 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. doi:10.1093/nar/gky1179 0305-1048 https://hdl.handle.net/10356/86025 http://hdl.handle.net/10220/49248 10.1093/nar/gky1179 en Nucleic Acids Research © 2018 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 9 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic G-quadruplex
PARP1 Promoter
Science::Chemistry
spellingShingle G-quadruplex
PARP1 Promoter
Science::Chemistry
Chambers, Vicki S.
Di Antonio, Marco
Sengar, Anjali
Balasubramanian, Shankar
Phan, Anh Tuân
Winnerdy, Fernaldo Richtia
Vandana, J. Jeya
Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
description 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.
author2 School of Physical and Mathematical Sciences
author_facet School of Physical and Mathematical Sciences
Chambers, Vicki S.
Di Antonio, Marco
Sengar, Anjali
Balasubramanian, Shankar
Phan, Anh Tuân
Winnerdy, Fernaldo Richtia
Vandana, J. Jeya
format Article
author Chambers, Vicki S.
Di Antonio, Marco
Sengar, Anjali
Balasubramanian, Shankar
Phan, Anh Tuân
Winnerdy, Fernaldo Richtia
Vandana, J. Jeya
author_sort Chambers, Vicki S.
title Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
title_short Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
title_full Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
title_fullStr Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
title_full_unstemmed Structure of a (3+1) hybrid G-quadruplex in the PARP1 promoter
title_sort structure of a (3+1) hybrid g-quadruplex in the parp1 promoter
publishDate 2019
url https://hdl.handle.net/10356/86025
http://hdl.handle.net/10220/49248
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