Effect of PI3-kinase inhibitors on DNA double strand break repair pathways: observations using a site specific DSB induction system.

IF 0.8 4区 环境科学与生态学 Q4 ENVIRONMENTAL SCIENCES Radiation protection dosimetry Pub Date : 2024-11-13 DOI:10.1093/rpd/ncae074
Tomoki Myodo, Yuki Sakamoto, Keita Sato, Honami Kobayashi, Kenta Iijima, Kenshi Komatsu, Shinya Matsuura, Hiroshi Tauchi
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Abstract

We established two types of site-specific DNA double strand breaks (DSB) induction systems to elucidate factors which affect the efficiency or quality of DSB repair. For mutation assays, a site specific DSB was generated by the transient expression of a zinc finger nuclease which targets the human HPRT1 gene. A cell line in which time and site specific DSBs can be generated in a HR reporter construct was used for homology-directed repair (HR) analysis. By using these two systems, we investigated the effects of PI3-kinase inhibitors on the efficiency and quality of DSB repair. Ataxia telangiectasia mutated (ATM) kinase inhibition resulted a decrease in mutant frequency and a slight increase in deletion-type mutations accompanied by microhomology. Furthermore, the HR frequency increased significantly when ATM kinase activity was inhibited. Thus, ATM kinase activity might be involved in the suppression of DSB end resection, and this may promote DSB repair through canonical non-homologous end joining.

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PI3-激酶抑制剂对 DNA 双股断裂修复途径的影响:使用特定位点 DSB 诱导系统进行观察。
我们建立了两种位点特异性DNA双链断裂(DSB)诱导系统,以阐明影响DSB修复效率或质量的因素。在突变检测中,通过瞬时表达靶向人类 HPRT1 基因的锌指核酸酶产生位点特异性 DSB。在HR报告基因构建体中可产生时间和位点特异性DSB的细胞系被用于同源定向修复(HR)分析。通过使用这两个系统,我们研究了 PI3 激酶抑制剂对 DSB 修复效率和质量的影响。抑制共济失调毛细血管扩张症突变体(ATM)激酶会降低突变频率,并略微增加伴随微同源的缺失型突变。此外,当ATM激酶活性受到抑制时,HR频率明显增加。因此,ATM激酶的活性可能参与了抑制DSB末端切除的过程,这可能会通过规范的非同源末端连接促进DSB修复。
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来源期刊
Radiation protection dosimetry
Radiation protection dosimetry 环境科学-公共卫生、环境卫生与职业卫生
CiteScore
1.40
自引率
10.00%
发文量
223
审稿时长
6-12 weeks
期刊介绍: Radiation Protection Dosimetry covers all aspects of personal and environmental dosimetry and monitoring, for both ionising and non-ionising radiations. This includes biological aspects, physical concepts, biophysical dosimetry, external and internal personal dosimetry and monitoring, environmental and workplace monitoring, accident dosimetry, and dosimetry related to the protection of patients. Particular emphasis is placed on papers covering the fundamentals of dosimetry; units, radiation quantities and conversion factors. Papers covering archaeological dating are included only if the fundamental measurement method or technique, such as thermoluminescence, has direct application to personal dosimetry measurements. Papers covering the dosimetric aspects of radon or other naturally occurring radioactive materials and low level radiation are included. Animal experiments and ecological sample measurements are not included unless there is a significant relevant content reason.
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