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电离辐射诱导的 DSB 处 Ku70/80 和 DNA-PKcs 的动态变化依赖于损伤的复杂性。

The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage.

机构信息

Department of Oncology, Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford OX3 7DQ, UK.

出版信息

Nucleic Acids Res. 2012 Nov;40(21):10821-31. doi: 10.1093/nar/gks879. Epub 2012 Sep 24.

DOI:10.1093/nar/gks879
PMID:23012265
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3510491/
Abstract

DNA double-strand breaks (DSBs) are biologically one of the most important cellular lesions and possess varying degrees of chemical complexity. The notion that the repairability of more chemically complex DSBs is inefficient led to the concept that the extent of DSB complexity underlies the severity of the biological consequences. The repair of DSBs by non-homologous end joining (NHEJ) has been extensively studied but it remains unknown whether more complex DSBs require a different sub-set of NHEJ protein for their repair compared with simple DSBs. To address this, we have induced DSBs in fluorescently tagged mammalian cells (Ku80-EGFP, DNA-PKcs-YFP or XRCC4-GFP, key proteins in NHEJ) using ultra-soft X-rays (USX) or multi-photon near infrared (NIR) laser irradiation. We have shown in real-time that simple DSBs, induced by USX or NIR microbeam irradiation, are repaired rapidly involving Ku70/80 and XRCC4/Ligase IV/XLF. In contrast, DSBs with greater chemical complexity are repaired slowly involving not only Ku70/80 and XRCC4/Ligase IV/XLF but also DNA-PKcs. Ataxia telangiectasia-mutated inhibition only retards repair of the more chemically complex DSBs which require DNA-PKcs. In summary, the repair of DSBs by NHEJ is highly regulated with pathway choice and kinetics of repair dependent on the chemical complexity of the DSB.

摘要

DNA 双链断裂 (DSB) 是生物学上最重要的细胞损伤之一，具有不同程度的化学复杂性。人们认为，更具化学复杂性的 DSB 修复效率较低，这导致了 DSB 复杂性的程度是生物后果严重程度的基础这一概念。非同源末端连接 (NHEJ) 修复 DSB 已得到广泛研究，但尚不清楚与简单 DSB 相比，更复杂的 DSB 是否需要一组不同的 NHEJ 蛋白进行修复。为了解决这个问题，我们使用超软 X 射线 (USX) 或多光子近红外 (NIR) 激光照射，在荧光标记的哺乳动物细胞 (Ku80-EGFP、DNA-PKcs-YFP 或 XRCC4-GFP，NHEJ 的关键蛋白) 中诱导 DSB。我们实时显示，USX 或 NIR 微束照射诱导的简单 DSB 快速修复，涉及 Ku70/80 和 XRCC4/Ligase IV/XLF。相比之下，具有更大化学复杂性的 DSB 修复缓慢，不仅涉及 Ku70/80 和 XRCC4/Ligase IV/XLF，还涉及 DNA-PKcs。共济失调毛细血管扩张突变抑制仅延迟需要 DNA-PKcs 的更具化学复杂性的 DSB 的修复。总之，NHEJ 修复 DSB 的过程受到高度调控，修复途径的选择和修复动力学取决于 DSB 的化学复杂性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/ada666a9b360/gks879f7p.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/386ca3569448/gks879f6p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/ada666a9b360/gks879f7p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/f80caa10885c/gks879f1p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/ffb566f1a0f3/gks879f2p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/ec963808c7fa/gks879f3p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/09d560216ae5/gks879f4p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/1d33ab4ee5ab/gks879f5p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/386ca3569448/gks879f6p.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/767c/3510491/ada666a9b360/gks879f7p.jpg

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