氧化應(yīng)激是導(dǎo)致許多嚴(yán)重疾病如癌癥、阿爾茨海默氏癥,、動脈硬化及糖尿病的元兇,。當(dāng)身體暴露于過量的電荷或者極強的氧化物中時，氧化應(yīng)激便會發(fā)生,。這些通常是在呼吸或其他代謝過程中發(fā)生,，在持續(xù)的壓力、暴露于紫外線或X射線時同樣也會出現(xiàn)氧化應(yīng)激,。如果氧化應(yīng)激過于強烈,，它將壓倒機體的天然防御。這些強勁的氧化物能破壞遺傳物質(zhì),，導(dǎo)致DNA產(chǎn)生一種有害的8-氧-鳥嘌呤堿基突變,。
DNA修復(fù)機制解碼
Enni Markkanen與牛津大學(xué)合作，解碼并分析了突變DNA堿基的修復(fù)機制,。這種機制有效的復(fù)制了數(shù)以千計的8-氧-鳥嘌呤而沒有它們有害的突變,，因此自然地避免了8-氧-鳥嘌呤損傷的負面后果。在發(fā)表于國家科學(xué)院刊的文章中,，研究者詳細描述了這種修復(fù)機制在時間和空間上的協(xié)調(diào)過程,。
Ulrich Hubscher教授希望這項基礎(chǔ)研究可以被應(yīng)用于治療。"我們希望這兒發(fā)現(xiàn)的DNA修復(fù)機制能帶來更少侵害的癌癥治療方法,，它有望為某些類型癌癥的早期檢查開發(fā)出新的檢測方法,。"與蘇黎世大學(xué)醫(yī)院合作的一項研究已經(jīng)展開，合作涉及在不同類型癌癥樣本中檢測基因的修復(fù)及其調(diào)控,。（生物谷bioon.com）
doi:10.1073/pnas.1110449109
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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.
