School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Nucleic Acids Res. 2019 Feb 20;47(3):1564-1572. doi: 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 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.
聚（ADP-核糖）聚合酶 1（PARP1）因其在 DNA 修复过程中的关键作用，已成为癌症治疗的一个有吸引力的靶点。在 BRCA 突变型癌症中抑制 PARP1 已被观察到具有临床益处。最近的基因组图谱实验已经确定了 PARP1 启动子内含有凸起的非经典 G-四链体形成序列。结构特征，如凸起，为选择性地靶向 PARP1 启动子内的非经典 G-四链体结构提供了机会，这可能成为调节 PARP1 表达的另一种治疗方法。在这里，我们报告了 PARP1 启动子中 23 个核苷酸富含 G 的序列形成的 G-四链体结构。我们的研究揭示了一种三层的分子内（3+1）杂交 G-四链体支架，其中三个链朝一个方向取向，第四个链朝相反方向取向。这种结构具有独特的结构特征，如腺嘌呤凸起和在中央边对环、推进器环和 5'侧翼末端之间形成的 G·G·T 碱基三链帽结构。鉴于 PARP1 在 DNA 修复和癌症干预中的重要作用，这种结构为通过 G-四链体 DNA 靶向探索 PARP1 抑制的治疗潜力提供了一个有吸引力的机会。
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