HAMNO 对 RPA 的化学抑制通过阻碍 DNA 复制和 G2 到 M 的转变来改变细胞周期动力学，但对辐射诱导的 DNA 损伤反应几乎没有影响,International Journal of Molecular Sciences

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HAMNO 对 RPA 的化学抑制通过阻碍 DNA 复制和 G2 到 M 的转变来改变细胞周期动力学，但对辐射诱导的 DNA 损伤反应几乎没有影响
International Journal of Molecular Sciences ( IF 4.9 ) Pub Date : 2023-10-06 , DOI: 10.3390/ijms241914941
Rositsa Dueva _{1,

2} , Lisa Marie Krieger _{1,

3} , Fanghua Li _{1,

4} , Daxian Luo _{1,

3} , Huaping Xiao _{1,

3} , Martin Stuschke _{3,

5,

6} , Eric Metzen ₂ , George Iliakis _{1,

3}

Affiliation

复制蛋白 A (RPA) 是主要的单链 DNA (ssDNA) 结合蛋白，对于 DNA 复制和通过同源定向修复途径处理 DNA 双链断裂 (DSB) 至关重要。最近，已经开发出针对 RPA70 亚基的小分子抑制剂，并防止 RPA 与 ssDNA 和各种 DNA 修复蛋白相互作用。这一发展的基本原理是此类化合物作为癌症治疗剂的潜在用途，因为它们能够抑制维持肿瘤生长的 DNA 复制。在这些化合物中，(1Z)-1-[(2-羟基苯胺基)亚甲基]萘-2-酮 (HAMNO) 已得到更广泛的研究，其抗肿瘤生长的功效被证明是由相关的 DNA 复制应激引起的。在这里，我们研究了 HAMNO 对暴露于电离辐射 (IR) 的细胞的影响，重点关注对 DNA 损伤反应和 DSB 加工的影响，并探索其作为放射增敏剂的潜力。我们发现 HAMNO 本身可以通过显着减少 DNA 合成来减慢细胞周期的进程。值得注意的是，HAMNO 还通过仍有待阐明的机制减弱 G2 期细胞进入有丝分裂的进程。此外，HAMNO 会增加 S 期而非 G2 期细胞中染色质结合 RPA 的比例，并通过同源重组抑制 DSB 修复。尽管对细胞周期和 DNA 损伤反应有这些显着影响，但在指数生长的培养物中或在富含 G2 期细胞的培养物中都无法检测到放射增敏作用。我们的结果补充了 RPA 抑制剂（特别是 HAMNO）的现有数据，并表明它们通过复制应激诱导的抗肿瘤活性可能不会延伸到放射增敏。然而，它可能通过合成致命的相互作用使细胞更容易受到其他形式的 DNA 损伤剂的影响，这需要进一步研究。

"点击查看英文标题和摘要"

Chemical Inhibition of RPA by HAMNO Alters Cell Cycle Dynamics by Impeding DNA Replication and G2-to-M Transition but Has Little Effect on the Radiation-Induced DNA Damage Response

Replication protein A (RPA) is the major single-stranded DNA (ssDNA) binding protein that is essential for DNA replication and processing of DNA double-strand breaks (DSBs) by homology-directed repair pathways. Recently, small molecule inhibitors have been developed targeting the RPA70 subunit and preventing RPA interactions with ssDNA and various DNA repair proteins. The rationale of this development is the potential utility of such compounds as cancer therapeutics, owing to their ability to inhibit DNA replication that sustains tumor growth. Among these compounds, (1Z)-1-[(2-hydroxyanilino) methylidene] naphthalen-2-one (HAMNO) has been more extensively studied and its efficacy against tumor growth was shown to arise from the associated DNA replication stress. Here, we study the effects of HAMNO on cells exposed to ionizing radiation (IR), focusing on the effects on the DNA damage response and the processing of DSBs and explore its potential as a radiosensitizer. We show that HAMNO by itself slows down the progression of cells through the cell cycle by dramatically decreasing DNA synthesis. Notably, HAMNO also attenuates the progression of G2-phase cells into mitosis by a mechanism that remains to be elucidated. Furthermore, HAMNO increases the fraction of chromatin-bound RPA in S-phase but not in G2-phase cells and suppresses DSB repair by homologous recombination. Despite these marked effects on the cell cycle and the DNA damage response, radiosensitization could neither be detected in exponentially growing cultures, nor in cultures enriched in G2-phase cells. Our results complement existing data on RPA inhibitors, specifically HAMNO, and suggest that their antitumor activity by replication stress induction may not extend to radiosensitization. However, it may render cells more vulnerable to other forms of DNA damaging agents through synthetically lethal interactions, which requires further investigation.

更新日期：2023-10-06

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