Elena Robeska , Kévin Lalanne , François Vianna , Haser Hasan Sutcu , Andriy Khobta , Didier Busso , J. Pablo Radicella , Anna Campalans , Céline Baldeyron
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引用次数: 0
Abstract
DNA is the major target of radiation therapy of malignant tumors. Ionizing radiation (IR) induces a variety of DNA lesions, including chemically modified bases and strand breaks. The use of proton beam therapy for cancer treatment is ramping up, as it is expected to reduce normal tissue damage. Thus, it is important to understand the molecular mechanisms of recognition, signaling, and repair of DNA damage induced by protons in the perspective of assessing not only the risk associated with human exposure to IR but also the possibility to improve the efficacy of therapy. Here, we used targeted irradiation of nuclear regions of living cells with controlled number of protons at a high spatio-temporal resolution to detect the induced base lesions and characterize the recruitment kinetics of the specific DNA glycosylases to DNA damage sites. We show that localized irradiation with 4 MeV protons induces, in addition to DNA double strand breaks (DSBs), the oxidized bases 7,8-dihydro-8-oxoguanine (8-oxoG) and thymine glycol (TG) at the site of irradiation. Consistently, the DNA glycosylases OGG1 and NTH1, capable of excising 8-oxoG and TG, respectively, and initiating the base excision repair (BER) pathway, are recruited to the site of damage. To our knowledge, this is the first direct evidence indicating that proton microbeams induce oxidative base damage, and thus implicating BER in the repair of DNA lesions induced by protons.
质子微束的定向核辐照会诱导 DNA 碱基氧化损伤,并引发 DNA 糖基化酶 OGG1 和 NTH1 的招募
DNA 是恶性肿瘤放射治疗的主要靶标。电离辐射(IR)会诱发各种 DNA 病变,包括碱基化学修饰和链断裂。由于质子束疗法有望减少对正常组织的损伤,质子束疗法在癌症治疗中的应用正在不断增加。因此,了解质子诱导的 DNA 损伤的识别、信号传导和修复的分子机制非常重要,这不仅能评估人类暴露于红外线的相关风险,还能提高治疗效果。在这里,我们使用高时空分辨率的可控质子对活细胞核区域进行定向辐照,以检测诱导的碱基病变,并描述特定 DNA 糖基化酶在 DNA 损伤位点的招募动力学。我们的研究表明,4MeV质子的局部辐照除了诱导DNA双链断裂(DSB)外,还在辐照部位诱导氧化碱基7,8-二氢-8-氧鸟嘌呤(8-oxoG)和胸腺嘧啶乙二醇(TG)。DNA 糖基化酶 OGG1 和 NTH1 被招募到损伤部位,它们能够分别切除 8-oxoG 和 TG,并启动碱基切除修复(BER)途径。据我们所知,这是第一个直接证据表明质子微束会诱导氧化碱基损伤,从而使 BER 与质子诱导的 DNA 损伤修复产生联系。
期刊介绍:
DNA Repair provides a forum for the comprehensive coverage of DNA repair and cellular responses to DNA damage. The journal publishes original observations on genetic, cellular, biochemical, structural and molecular aspects of DNA repair, mutagenesis, cell cycle regulation, apoptosis and other biological responses in cells exposed to genomic insult, as well as their relationship to human disease.
DNA Repair publishes full-length research articles, brief reports on research, and reviews. The journal welcomes articles describing databases, methods and new technologies supporting research on DNA repair and responses to DNA damage. Letters to the Editor, hot topics and classics in DNA repair, historical reflections, book reviews and meeting reports also will be considered for publication.