Impact of ribonucleotide incorporation by DNA polymerases β and λ on oxidative base excision repair.
Impact of ribonucleotide incorporation by DNA polymerases β and λ on oxidative base excision repair.
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DOI：
10.1038/ncomms10805
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发表时间：
2016-02-26
影响因子：
16.6
通讯作者：
Maga G
中科院分区：
文献类型：
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作者：
Crespan E;Furrer A;Rösinger M;Bertoletti F;Mentegari E;Chiapparini G;Imhof R;Ziegler N;Sturla SJ;Hübscher U;van Loon B;Maga G
氧化应激是 DNA 损伤的常见来源。许多细胞 DNA 聚合酶 (Pols) 可以在 DNA 合成过程中掺入核糖核苷酸 (rNMP)。然而，氧化应激触发的 DNA 修复合成是否有助于基因组 rNMPs 的掺入目前尚不完全清楚。人类特化的 Pols β 和 λ 是参与氧化应激耐受的重要酶，在碱基切除修复和经过非常频繁的氧化损伤 7,8-二氢-8-氧代鸟嘌呤 (8-oxo-G) 的跨损伤合成中发挥作用。我们发现 Pol β 比 Pol λ 可以更大程度地结合与正常碱基或 8-oxo-G 相反的 rNMP，并且具有不同的保真度。此外，与 8-oxo-G 相对的 rNMP 的掺入延迟了 DNA 糖基化酶的修复。对 Pol β 和 λ 缺陷细胞提取物的研究表明，Pol β 水平可以极大地影响 rNMP 掺入，从而对抗氧化性 DNA 损伤。 氧化应激是 DNA 损伤的常见来源，可通过碱基切除修复机制（包括聚合酶 β）进行修复。在这里，作者发现聚合酶 beta 以及较小程度的 lambda 在合成过程中可能会错误地掺入核糖核苷酸。
Oxidative stress is a very frequent source of DNA damage. Many cellular DNA polymerases (Pols) can incorporate ribonucleotides (rNMPs) during DNA synthesis. However, whether oxidative stress-triggered DNA repair synthesis contributes to genomic rNMPs incorporation is so far not fully understood. Human specialized Pols β and λ are the important enzymes involved in the oxidative stress tolerance, acting both in base excision repair and in translesion synthesis past the very frequent oxidative lesion 7,8-dihydro-8-oxoguanine (8-oxo-G). We found that Pol β, to a greater extent than Pol λ can incorporate rNMPs opposite normal bases or 8-oxo-G, and with a different fidelity. Further, the incorporation of rNMPs opposite 8-oxo-G delays repair by DNA glycosylases. Studies in Pol β- and λ-deficient cell extracts suggest that Pol β levels can greatly affect rNMP incorporation opposite oxidative DNA lesions. Oxidative stress is a common source of DNA damage and is repaired by the base excision repair machinery, including polymerase beta. Here the authors find that polymerase beta, and to a lesser extent lambda, can mistakenly incorporate ribonucleotides during synthesis.