AbstractHydroxyurea (HU; hydroxycarbamide) is a chemotherapy medication used to treat various types of cancer and other diseases such as sickle cell anemia. HU inhibits DNA synthesis by targeting ribonucleotide reductase (RNR). Recent studies have suggested that HU also causes oxidative stress in living systems.

摘要羟基脲（HU；羟基脲）是一种化疗药物，用于治疗各种类型的癌症和其他疾病，如镰状细胞性贫血。HU通过靶向核糖核苷酸还原酶（RNR）抑制DNA合成。最近的研究表明，HU还会导致生命系统中的氧化应激。

In the present study, we investigated if HU could directly affect the activity and/or conformation of DNA. We measured in vitro gene expression in the presence of HU by adapting a cell-free luciferase assay. HU exhibited a bimodal effect on gene expression, where promotion or inhibition were observed at lower or higher concentrations (mM range), respectively.

在本研究中，我们调查了HU是否可以直接影响DNA的活性和/或构象。我们通过采用无细胞荧光素酶测定法测量了HU存在下的体外基因表达。HU对基因表达表现出双峰效应，其中分别在较低或较高浓度（mM范围）下观察到促进或抑制。

Using atomic force microscopy (AFM), the higher-order structure of DNA was revealed to be partially-thick with kinked-branching structures after HU was added. An elongated coil conformation was observed by AFM in the absence of HU. Single DNA molecules in bulk aqueous solution under fluctuating Brownian motion were imaged by fluorescence microscopy (FM).

使用原子力显微镜（AFM），添加HU后，发现DNA的高阶结构部分较厚，具有扭结的分支结构。在不存在HU的情况下，通过AFM观察到细长的螺旋构象。通过荧光显微镜（FM）对波动的布朗运动下的大量水溶液中的单个DNA分子进行成像。

Both spring and damping constants, mechanical properties of DNA, increased when HU was added. These experimental investigations indicate that HU directly interacts with DNA and provide new insights into how HU acts as a chemotherapeutic agent and targets other diseases..

加入HU后，DNA的弹簧常数和阻尼常数（力学性能）均增加。这些实验研究表明，HU直接与DNA相互作用，并为HU如何作为化学治疗剂和靶向其他疾病提供了新的见解。。

IntroductionHydroxyurea (HU), or hydroxycarbamide, is an antitumor drug1,2,3,4,5 used to treat chronic myeloid leukemia and certain types of head and neck cancer6,7. HU is also the primary drug of choice for the treatment of sickle cell anemia3,7,8. A promising new indication for HU in treating Alzheimer's disease has recently attracted much attention for its ability to prevent cognitive decline9.Antitumor activity of HU was first reported in the 1960s6,10.

简介羟基脲（HU）或羟基脲是一种抗肿瘤药物1,2,3,4,5，用于治疗慢性粒细胞白血病和某些类型的头颈癌6,7。HU也是治疗镰状细胞贫血的首选药物3,7,8。HU治疗阿尔茨海默病的一个有前途的新适应症最近因其预防认知衰退的能力而备受关注9。HU的抗肿瘤活性于20世纪60年代首次报道6,10。

HU inactivates ribonucleotide reductase (RNR), causing a decrease in the cellular pool of deoxyribonucleoside triphosphates, which leads to the inhibition of DNA synthesis11,12,13,14,15,16. Recently, experiments using budding and fission yeasts reported that HU globally inhibited RNA synthesis and transcription by RNA polymerase17.

HU使核糖核苷酸还原酶（RNR）失活，导致脱氧核糖核苷三磷酸的细胞库减少，从而导致DNA合成的抑制11,12,13,14,15,16。最近，使用发芽和裂变酵母的实验报道，HU通过RNA聚合酶17全面抑制RNA合成和转录17。

Therefore, the cytotoxic and antitumor activities of HU have been attributed to enzyme-mediated effects. However, little work has been conducted on the direct interaction of HU with DNA and its effects on gene expression. Even though HU is actively used medically to treat many diseases, the exact mechanism of how HU works is not fully known at present.To gain further insight into the exact biological mechanism of the action of HU, here we explored if HU could directly affect DNA activity (i.e., gene expression) and/or DNA conformation (i.e., DNA structure).

因此，HU的细胞毒性和抗肿瘤活性归因于酶介导的作用。然而，关于HU与DNA的直接相互作用及其对基因表达的影响的研究很少。尽管HU在医学上被积极用于治疗许多疾病，但目前尚不完全清楚HU的确切作用机制。为了进一步了解HU作用的确切生物学机制，我们在这里探讨了HU是否可以直接影响DNA活性（即基因表达）和/或DNA构象（即DNA结构）。

We used an in vitro gene expression luciferase assay to measure DNA activity in the presence of HU. Interestingly, we found that HU exhibited a bimodal effect on gene expression. Promotion was observed at lower concentrations of HU (< 10 mM), while inhibition of gene expression was discovered at higher concentrations (> 10 mM).

我们使用体外基因表达荧光素酶测定法来测量HU存在下的DNA活性。有趣的是，我们发现HU对基因表达表现出双峰效应。在较低浓度的HU（<10 mM）下观察到促进作用，而在较高浓度（>10 mM）下发现基因表达受到抑制。

In addition, a single molecular observation of genome-size DNA by atomic force microscopy (AFM) and fluorescen.

此外，通过原子力显微镜（AFM）和荧光对基因组大小的DNA进行了单分子观察。

(1)

(1)

where \(\overline{L }\) is the time-average of L, τ is the time lag between data points, and the symbol, <  > , means the average of the time-dependent variable. Figure 3D,E shows the calculated autocorrelation function (see also Fig. S2). Based on a simple theoretical model of fluctuation–dissipation theory for the thermal fluctuations under harmonic potential, the autocorrelation function is expressed as in Eq. (2)24,25:$$\begin{array}{*{20}c} {C\left( \tau \right)\sim \frac{{k_{B} T}}{k}e^{{ - \gamma \tau }} \cos \omega \tau } \\ \end{array}$$.

其中\（\ overline{L}\）是L的时间平均值，τ是数据点之间的时滞，符号 < >表示时间相关变量的平均值。图3D，E显示了计算出的自相关函数（另见图S2）。基于谐波势下热涨落的涨落耗散理论的简单理论模型，自相关函数表示为等式（2）24,25：$$\ begin{array}{*{20}c}{C \左（\ tau \右）\sim \ frac{{k\uu{B}T}{k}e^{-\gamma\tau}}\cos\omega\tau}\\ end{array}$$。

(2)

(2)

where \({k}_{B}\) is the Boltzmann constant, T is the absolute temperature (297 K in our observations), k (N/m) is the spring constant, γ (sec-1) is the damping constant, and ω is the angular frequency. Considering the relationship k ≈ \(\frac{{k}_{B}T}{C(0)}\), where C(0) is the value at τ = 0, the spring constant k can be evaluated from the initial value of the autocorrelation function.

在哪里\({k}_{B} \）是玻尔兹曼常数，T是绝对温度（在我们的观察中为297 K），K（N/m）是弹簧常数，γ（sec-1）是阻尼常数，ω是角频率。考虑到关系k≈\（\ frac{{k}_{B}T}{C（0）}\），其中C（0）是τ==0处的值，弹簧常数k可以从自相关函数的初始值计算。

The given fitting curve based on Eq. (2) is shown with a broken line (Fig. 3D,E and Fig. S3). From this analysis, the spring constants of single T4 GT7 DNA molecules are estimated as k0 = (20.1 ± 4.6) nN/m and kHU = (75.4 ± 15.9) nN/m with 0 mM and 15 mM HU, respectively.Figure 3Time-dependent fluctuation of single T4 GT7 DNA molecules under Brownian motion observed by fluorescence microscopy (FM).

基于等式（2）的给定拟合曲线用虚线表示（图3D，E和图S3）。根据该分析，单个T4 GT7 DNA分子的弹簧常数估计为k0=（20.1±4.6）nN/m和kHU=（75.4±15.9）nN/m，分别为0 mM和15 mM HU。图3通过荧光显微镜（FM）观察到布朗运动下单个T4 GT7 DNA分子的时间依赖性波动。

(A) Control (0 mM HU) and (B) 15 mM HU treated DNA. The time interval between neighboring frames is 0.3 s. The corresponding quasi-three-dimensional profiles of the fluorescence intensity distribution are shown on the lower frames of each image. Also see Fig. S3. (C) Left, schematic representation of the long-axis length L for the FM image of a single DNA molecule.

（A） 对照（0 mM HU）和（B）15 mM HU处理的DNA。相邻帧之间的时间间隔为0.3秒。荧光强度分布的相应准三维轮廓显示在每个图像的下帧上。另见图S3。（C） 左，单个DNA分子的FM图像的长轴长度L的示意图。

Right, time-dependent changes in L of T4 GT7 DNA molecules. The time trace lines are DNA without HU (blue, Control) and DNA with 15 mM HU (red). (D, E) Autocorrelation of the time-dependent fluctuation of the long-axis length of single T4 GT7 DNA molecules. The fitting curves were depicted based on Eq. 2.

正确的，T4 GT7 DNA分子L的时间依赖性变化。时间迹线是没有HU（蓝色，对照）的DNA和具有15 mM HU（红色）的DNA。（D，E）单个T4 GT7 DNA分子长轴长度的时间依赖性波动的自相关。拟合曲线基于等式2描绘。

Fluctuations were measured in the Tris–HCl buffer solution without HU (Control) and with 15 mM HU. At each condition, independent measurements for the fluctuation of single DNA observations by FM were performed at least three times.Full size imageFigure 4 shows changes in spring k and damping γ constants at differ.

在不含HU（对照）和15 mM HU的Tris-HCl缓冲溶液中测量波动。在每种条件下，通过FM对单个DNA观察值的波动进行独立测量至少三次。全尺寸图像图4显示了不同温度下弹簧k和阻尼γ常数的变化。

Data availability

数据可用性

All data presented in this study are contained within the article and Supplementary Materials.

本研究中提供的所有数据均包含在文章和补充材料中。

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Download referencesAcknowledgementsThis work was supported by grants awarded by the Japanese Society for the Promotion of Science (JSPS) to T. Kenmotsu (KAKENHI grant number 20H05934), T.N. (KAKENHI grant number JP22K20640 and JP23K14159) and K.Y. (KAKENHI grant number JP20H01877). We thank for the cooperation of CD measurement by Miyatake Toshimune.Author informationAuthors and AffiliationsFaculty of Life and Medical Sciences, Doshisha University, Kyoto, 610-0394, JapanHaruto Ogawa, Takashi Nishio, Yuko Yoshikawa, Koichiro Sadakane, Takahiro Kenmotsu & Kenichi YoshikawaCluster of Excellence Physics of Life, TUD Dresden University of Technology, 01307, Dresden, GermanyTakashi NishioDepartment of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University, Kyoto, 610-0321, JapanTomoyuki KogaCenter for Integrative Medicine and Physics, Institute for Advanced Study, Kyoto University, Kyoto, 606-8501, JapanKenichi YoshikawaAuthorsHaruto OgawaView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了日本科学促进会（JSPS）授予T.Kenmotsu（KAKENHI grant number 20H05934），T.N.（KAKENHI grant number JP22K20640和JP23K14159）和K.Y.（KAKENHI grant number JP20H01877）的资助。我们感谢Miyatake Toshimune在CD测量方面的合作。作者信息作者和附属机构京都多西沙大学生命与医学科学学院，610-0394，日本小川，西雄，吉川由子，佐丹光一郎，高弘·剑莫措和吉川贤一生命物理卓越大学，都德德累斯顿理工大学，01307，德累斯顿，德国多西沙大学科学与工程学院分子化学与生物化学系，京都，610-0321，日本东京大学综合医学与物理研究所，京都，606606606606 0-8501，JapanKenichi YoshikawaAuthorsHaruto OgawaView作者出版物您也可以在中搜索该作者。

PubMed Google ScholarTakashi NishioView author publicationsYou can also search for this author in

PubMed Google ScholarTakashi NishioView作者出版物您也可以在

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PubMed Google ScholarKoichiro SadakaneView author publicationsYou can also search for this author in

PubMed Google ScholarKoichiro SadakaneView作者出版物您也可以在

PubMed Google ScholarTakahiro KenmotsuView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsH.O, T.N., Y.Y. and K.Y. designed the study. H.O., T.N. and Y.Y. performed the experiments and analyzed the data. K.S., T.K., T.K. and K.Y. supervised the experiments and interpretation in the manuscript. H.O, T.N., Y.Y. and K.Y. wrote the manuscript.

PubMed谷歌学术贡献。O、 T.N.，Y.Y.和K.Y.设计了这项研究。H、 O.，T.N.和Y.Y.进行了实验并分析了数据。K、 S.，T.K.，T.K.和K.Y.监督了手稿中的实验和解释。H、 O，T.N.，Y.Y.和K.Y.撰写了手稿。

All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.Corresponding authorCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleOgawa, H., Nishio, T., Yoshikawa, Y. et al. Characteristic effect of hydroxyurea on the higher-order structure of DNA and gene expression.

转载和许可本文引用本文Ogawa，H.，Nishio，T.，Yoshikawa，Y。等人。羟基脲对DNA高级结构和基因表达的特征效应。

Sci Rep 14, 13826 (2024). https://doi.org/10.1038/s41598-024-64538-yDownload citationReceived: 01 February 2024Accepted: 10 June 2024Published: 15 June 2024DOI: https://doi.org/10.1038/s41598-024-64538-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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