辐射产生的短 DNA 片段可能会干扰非同源末端连接并诱导基因组不稳定性。
Radiation-generated short DNA fragments may perturb non-homologous end-joining and induce genomic instability.
机构信息
Department of Radiation Medicine, Georgetown University Medical Center, USA.
出版信息
J Radiat Res. 2011;52(3):309-19. doi: 10.1269/jrr.10147.
Abstract
Cells exposed to densely ionizing radiation (high-LET) experience more severe biological damage than do cells exposed to sparsely ionizing radiation (low-LET). The prevailing hypothesis is that high-LET radiations induce DNA double strand-breaks (DSB) that are more complex and clustered, and are thereby more challenging to repair. Here, we present experimental data obtained by atomic force microscopy imaging, DNA-dependent protein kinase (DNA-PK) activity determination, DNA ligation assays, and genomic studies to suggest that short DNA fragments are important products of radiation-induced DNA lesions, and that the lengths of DNA fragments may be significant in the cellular responses to ionizing radiation. We propose the presence of a subset of short DNA fragments that may affect cell survival and genetic stability following exposure to ionizing radiation, and that the enhanced biological effects of high-LET radiation may be explained, in part, by the production of increased quantities of short DNA fragments.
摘要
细胞暴露于高传能线密度（high-LET）辐射下会经历比低传能线密度（low-LET）辐射更严重的生物损伤。主流假说是高 LET 射线诱导的 DNA 双链断裂（DSB）更复杂且更聚集，因此更难修复。在这里，我们通过原子力显微镜成像、DNA 依赖性蛋白激酶（DNA-PK）活性测定、DNA 连接测定和基因组研究提供了实验数据，表明短 DNA 片段是辐射诱导的 DNA 损伤的重要产物，并且 DNA 片段的长度在细胞对电离辐射的反应中可能具有重要意义。我们提出存在一小部分短 DNA 片段，这些片段可能会影响细胞在暴露于电离辐射后的存活和遗传稳定性，并且高 LET 辐射的增强的生物学效应部分可以通过产生更多数量的短 DNA 片段来解释。
相似文献
1
Radiation-generated short DNA fragments may perturb non-homologous end-joining and induce genomic instability.辐射产生的短 DNA 片段可能会干扰非同源末端连接并诱导基因组不稳定性。
J Radiat Res. 2011;52(3):309-19. doi: 10.1269/jrr.10147.
2
Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy.成簇 DNA 双链断裂：生物学效应及其与癌症放射治疗的相关性。
Genes (Basel). 2020 Jan 15;11(1):99. doi: 10.3390/genes11010099.
3
Lysines 3241 and 3260 of DNA-PKcs are important for genomic stability and radioresistance.DNA依赖蛋白激酶催化亚基（DNA-PKcs）的赖氨酸3241和赖氨酸3260对基因组稳定性和辐射抗性至关重要。
Biochem Biophys Res Commun. 2016 Aug 19;477(2):235-40. doi: 10.1016/j.bbrc.2016.06.048. Epub 2016 Jun 11.
4
The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation.依赖Ku蛋白的非同源末端连接修复途径而非其他修复途径会受到高线性能量传递电离辐射的抑制。
DNA Repair (Amst). 2008 May 3;7(5):725-33. doi: 10.1016/j.dnarep.2008.01.010. Epub 2008 Mar 5.
5
Distribution of double-strand breaks induced by ionizing radiation at the level of single DNA molecules examined by atomic force microscopy.通过原子力显微镜在单DNA分子水平检测电离辐射诱导的双链断裂分布。
Radiat Res. 2009 Sep;172(3):288-95. doi: 10.1667/RR1772.1.
6
Evidence for complexity at the nanometer scale of radiation-induced DNA DSBs as a determinant of rejoining kinetics.辐射诱导的DNA双链断裂在纳米尺度上的复杂性作为重新连接动力学决定因素的证据。
Radiat Res. 2005 Jul;164(1):73-85. doi: 10.1667/rr3394.
7
The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation--no simple task.环境相关的高线性能量转移辐射引起的 DNA 双链断裂的修复——并非易事。
DNA Repair (Amst). 2014 May;17:64-73. doi: 10.1016/j.dnarep.2014.01.014. Epub 2014 Feb 22.
8
DNA fragments induction in human fibroblasts by radiations of different qualities.
Radiat Prot Dosimetry. 2006;122(1-4):166-8. doi: 10.1093/rpd/ncl389. Epub 2006 Dec 2.
9
Formation of clustered DNA damage in vivo upon irradiation with ionizing radiation: Visualization and analysis with atomic force microscopy.离子辐射照射后体内聚集性 DNA 损伤的形成：原子力显微镜的可视化和分析。
Proc Natl Acad Sci U S A. 2022 Mar 29;119(13):e2119132119. doi: 10.1073/pnas.2119132119. Epub 2022 Mar 24.
10
Quantification of radiation induced DNA double-strand breaks in human fibroblasts by PFGE: testing the applicability of random breakage models.通过脉冲场凝胶电泳对人成纤维细胞中辐射诱导的DNA双链断裂进行定量分析：测试随机断裂模型的适用性。
Int J Radiat Biol. 2002 May;78(5):375-88. doi: 10.1080/09553000110110941.
引用本文的文献
1
PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy.聚（ADP - 核糖）聚合酶（PARP）抑制使BRCA1野生型和突变型乳腺癌对质子治疗产生放射增敏作用。
Sci Rep. 2024 Dec 28;14(1):30897. doi: 10.1038/s41598-024-81914-w.
2
Cosmic Ionizing Radiation: A DNA Damaging Agent That May Underly Excess Cancer in Flight Crews.宇宙辐射：一种可能导致飞行机组人员癌症发病率上升的 DNA 损伤剂。
Int J Mol Sci. 2024 Jul 12;25(14):7670. doi: 10.3390/ijms25147670.
3
Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors.质子或碳离子治疗联合 DNA 损伤修复抑制剂的潜在获益。
Cells. 2024 Jun 19;13(12):1058. doi: 10.3390/cells13121058.
4
Short Double-Stranded DNA (≤40-bp) Affects Repair Pathway Choice.短双链 DNA（≤40bp）影响修复途径选择。
Int J Mol Sci. 2023 Jul 23;24(14):11836. doi: 10.3390/ijms241411836.
5
The Cellular Response to Complex DNA Damage Induced by Ionising Radiation.细胞对电离辐射诱导的复杂 DNA 损伤的反应。
Int J Mol Sci. 2023 Mar 3;24(5):4920. doi: 10.3390/ijms24054920.
6
Boron Neutron Capture Therapy Eliminates Radioresistant Liver Cancer Cells by Targeting DNA Damage and Repair Responses.硼中子俘获疗法通过靶向DNA损伤和修复反应消除放射抗性肝癌细胞。
J Hepatocell Carcinoma. 2022 Dec 29;9:1385-1401. doi: 10.2147/JHC.S383959. eCollection 2022.
7
The high toxicity of DSB-clusters modelling high-LET-DNA damage derives from inhibition of c-NHEJ and promotion of alt-EJ and SSA despite increases in HR.模拟高传能线密度DNA损伤的双链断裂簇的高毒性源于对经典非同源末端连接的抑制以及对替代末端连接和单链退火的促进，尽管同源重组有所增加。
Front Cell Dev Biol. 2022 Oct 3;10:1016951. doi: 10.3389/fcell.2022.1016951. eCollection 2022.
8
Proton induced DNA double strand breaks at the Bragg peak: Evidence of enhanced LET effect.质子在布拉格峰处诱导的DNA双链断裂：高传能线密度效应增强的证据。
Front Oncol. 2022 Aug 5;12:930393. doi: 10.3389/fonc.2022.930393. eCollection 2022.
9
Chromatin and the Cellular Response to Particle Radiation-Induced Oxidative and Clustered DNA Damage.染色质与细胞对粒子辐射诱导的氧化和簇状DNA损伤的反应。
Front Cell Dev Biol. 2022 Jul 13;10:910440. doi: 10.3389/fcell.2022.910440. eCollection 2022.
10
DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks.电离辐射后 DNA 损伤的聚集及其对染色质断裂处理的后果。
Molecules. 2022 Feb 24;27(5):1540. doi: 10.3390/molecules27051540.
本文引用的文献
1
Base damage immediately upstream from double-strand break ends is a more severe impediment to nonhomologous end joining than blocked 3'-termini.双链断裂末端上游的基本损伤比对 3’端受阻更严重地阻碍非同源末端连接。
Radiat Res. 2011 Jan;175(1):97-112. doi: 10.1667/RR2332.1.
2
A Monte Carlo study of the radiation quality dependence of DNA fragmentation spectra.蒙特卡罗研究 DNA 碎片谱的辐射质量依赖性。
Radiat Res. 2010 Mar;173(3):263-71. doi: 10.1667/RR1957.1.
3
Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex.库和 DNA 依赖性蛋白激酶的动态构象和组装调节 DNA 结合和初始非同源末端连接复合物。
J Biol Chem. 2010 Jan 8;285(2):1414-23. doi: 10.1074/jbc.M109.065615. Epub 2009 Nov 5.
4
Small-molecule drugs mimicking DNA damage: a new strategy for sensitizing tumors to radiotherapy.模拟DNA损伤的小分子药物：使肿瘤对放疗敏感的新策略。
Clin Cancer Res. 2009 Feb 15;15(4):1308-16. doi: 10.1158/1078-0432.CCR-08-2108. Epub 2009 Feb 3.
5
Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining.通过非同源末端连接修复电离辐射诱导的DNA双链断裂。
Biochem J. 2009 Feb 1;417(3):639-50. doi: 10.1042/BJ20080413.
6
Patterns of DNA copy number changes in sentinel lymph node breast cancer metastases.
Cytogenet Genome Res. 2008;122(1):16-21. doi: 10.1159/000151311. Epub 2008 Oct 14.
7
Eukaryotic DNA ligases: structural and functional insights.真核生物DNA连接酶：结构与功能见解
Annu Rev Biochem. 2008;77:313-38. doi: 10.1146/annurev.biochem.77.061306.123941.
8
The Ku-dependent non-homologous end-joining but not other repair pathway is inhibited by high linear energy transfer ionizing radiation.依赖Ku蛋白的非同源末端连接修复途径而非其他修复途径会受到高线性能量传递电离辐射的抑制。
DNA Repair (Amst). 2008 May 3;7(5):725-33. doi: 10.1016/j.dnarep.2008.01.010. Epub 2008 Mar 5.
9
Homologous recombination in DNA repair and DNA damage tolerance.DNA修复和DNA损伤耐受中的同源重组。
Cell Res. 2008 Jan;18(1):99-113. doi: 10.1038/cr.2008.1.
10
The endless tale of non-homologous end-joining.非同源末端连接的无尽故事。
Cell Res. 2008 Jan;18(1):114-24. doi: 10.1038/cr.2008.3.
Zotero 插件