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首页> 外文期刊>Oncogene >Nonhomologous end-joining of site-specific but not of radiation-induced DNA double-strand breaks is reduced in the presence of wild-type p53
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Nonhomologous end-joining of site-specific but not of radiation-induced DNA double-strand breaks is reduced in the presence of wild-type p53

机译：在野生型p53存在下，位点特异性而非辐射诱导的DNA双链断裂的非同源末端连接减少

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Nonhomologous end-joining (NHEJ) of DNA double-strand breaks (DSBs) entails two principal mechanisms: modification of DNA ends prior to ligation (error-prone rejoining) or precise ligation without modification if the DNA ends are complementary (error-free repair). Error-prone rejoining is mutagenic, because it can lead to destruction of coding sequence or to chromosomal aberrations, and therefore must be tightly regulated. Previous studies on the role of the p53 tumor suppressor in the regulation of NHEJ have yielded conflicting results, but a rigorous analysis of NHEJ proficiency and fidelity in a purely chromosomal context has not been carried out. To this end, we created novel repair plasmid substrates that integrate into the genome. DSBs generated by the I-SceI endonuclease within these substrates were repaired by either error-prone rejoining or precise ligation. We found that the expression of wild-type p53 inhibited any repair-associated DNA sequence deletion, including a more than 250-fold inhibition of error-prone rejoining events compared to p53-null cells, while any promoting effect of p53 on precise ligation could not be directly evaluated. The role of p53 in NHEJ appeared to involve a direct transactivation-independent mechanism, possibly restricting DNA end-modification by blocking the annealing of single strands along flanking stretches of microhomology. The inhibition of error-prone rejoining by p53 did not apply to the rejoining of DSBs induced by ionizing radiation. In conclusion, our data suggest that p53 restricts the mutagenic effects of NHEJ without compromising repair proficiency or cell survival, thereby maintaining genomic stability.
机译：DNA双链断裂（DSB）的非同源末端连接（NHEJ）涉及两个主要机制：连接前修饰DNA末端（容易出错的重新连接）;如果DNA末端是互补的，则无需修饰即可精确连接（无错误修复） ）。容易出错的重新连接是诱变的，因为它可能导致编码序列的破坏或染色体畸变，因此必须严格调节。先前有关p53抑癌基因在NHEJ调控中的作用的研究得出了相互矛盾的结果，但尚未对纯染色体背景下的NHEJ熟练度和保真度进行严格的分析。为此，我们创建了整合到基因组中的新型修复质粒底物。在这些底物中，I-SceI核酸内切酶产生的DSB可通过容易出错的重新连接或精确连接来修复。我们发现，野生型p53的表达抑制了任何与修复相关的DNA序列缺失，包括与p53无效细胞相比，对易错再结合事件的抑制超过250倍，而p53对精确连接的任何促进作用都可以不直接评估。 p53在NHEJ中的作用似乎涉及直接的反式激活机制，可能通过阻止沿微同源性侧翼延伸的单链退火来限制DNA末端修饰。 p53对易于出错的重新结合的抑制作用不适用于电离辐射诱导的DSB的重新结合。总之，我们的数据表明p53可以限制NHEJ的诱变作用，而不会损害修复能力或细胞存活率，从而保持基因组稳定性。

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