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PNAS:解密DNA氧化损伤的修复机制

  1. DNA氧化性损伤

来源:生物谷 2012-11-18 07:02

氧化应激是导致许多严重疾病如癌症、阿尔茨海默氏症、动脉硬化及糖尿病的元凶。当身体暴露于过量的电荷或者极强的氧化物中时,氧化应激便会发生。这些通常是在呼吸或其他代谢过程中发生,在持续的压力、暴露于紫外线或X射线时同样也会出现氧化应激。如果氧化应激过于强烈,它将压倒机体的天然防御。这些强劲的氧化物能破坏遗传物质,导致DNA产生一种有害的8-氧-鸟嘌呤碱基突变。

氧化应激是导致许多严重疾病如癌症、阿尔茨海默氏症、动脉硬化及糖尿病的元凶。当身体暴露于过量的电荷或者极强的氧化物中时,氧化应激便会发生。这些通常是在呼吸或其他代谢过程中发生,在持续的压力、暴露于紫外线或X射线时同样也会出现氧化应激。如果氧化应激过于强烈,它将压倒机体的天然防御。这些强劲的氧化物能破坏遗传物质,导致DNA产生一种有害的8-氧-鸟嘌呤碱基突变。

DNA修复机制解码

Enni Markkanen与牛津大学合作,解码并分析了突变DNA碱基的修复机制。这种机制有效的复制了数以千计的8-氧-鸟嘌呤而没有它们有害的突变,因此自然地避免了8-氧-鸟嘌呤损伤的负面后果。在发表于国家科学院刊的文章中,研究者详细描述了这种修复机制在时间和空间上的协调过程。

Ulrich Hubscher教授希望这项基础研究可以被应用于治疗。"我们希望这儿发现的DNA修复机制能带来更少侵害的癌症治疗方法,它有望为某些类型癌症的早期检查开发出新的检测方法。"与苏黎世大学医院合作的一项研究已经展开,合作涉及在不同类型癌症样本中检测基因的修复及其调控。(生物谷bioon.com)

Regulation of oxidative DNA damage repair by DNA polymerase λ and MutYH by crosstalk of phosphorylation and ubiquitination.

Enni Markkanen, Barbara van Loon, Elena Ferrari, Jason L. Parsons, Grigory L. Dianov, and Ulrich Hübscher.

Abstract: It is of pivotal importance for genome stability that repair DNA polymerases (Pols), such as Pols λ and β, which all exhibit considerably reduced fidelity when replicating undamaged DNA, are tightly regulated, because their misregulation could lead to mutagenesis. Recently, we found that the correct repair of the abundant and highly miscoding oxidative DNA lesion 7,8-dihydro-8-oxo-2′-deoxyguanine (8-oxo-G) is performed by an accurate repair pathway that is coordinated by the MutY glycosylase homologue (MutYH) and Pol λ in vitro and in vivo. Pol λ is phosphorylated by Cdk2/cyclinA in late S and G2 phases of the cell cycle, promoting Pol λ stability by preventing it from being targeted for proteasomal degradation by ubiquitination. However, it has remained a mystery how the levels of Pol λ are controlled, how phosphorylation promotes its stability, and how the engagement of Pol λ in active repair complexes is coordinated. Here, we show that the E3 ligase Mule mediates the degradation of Pol λ and that the control of Pol λ levels by Mule has functional consequences for the ability of mammalian cells to deal with 8-oxo-G lesions. Furthermore, we demonstrate that phosphorylation of Pol λ by Cdk2/cyclinA counteracts its Mule-mediated degradation by promoting recruitment of Pol λ to chromatin into active 8-oxo-G repair complexes through an increase in Pol λ’s affinity to chromatin-bound MutYH. Finally, MutYH appears to promote the stability of Pol λ by binding it to chromatin. In contrast, Pol λ not engaged in active repair on chromatin is subject for proteasomal degradation.

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