Molecular and biological roles of Ape1 protein in mammalian base excision repair
Molecular and biological roles of Ape1 protein in mammalian base excision repair
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DOI：
10.1016/j.dnarep.2005.09.004
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发表时间：
2005-12-08
期刊：
影响因子：
3.8
通讯作者：
Sung, JS
中科院分区：
文献类型：
--
作者：
Demple, B;Sung, JS
许多氧化性DNA损伤可以通过碱基切除修复（BER）得到很好的处理，但某些类型可能存在问题。最近的工作表明，2-脱氧核糖内酯（dL）是这样一个病变，形成稳定的，共价交联之间的脱碱基残基和DNA修复蛋白裂解酶活性。在DNA聚合酶β的情况下，通过Ape 1（主要的哺乳动物AP内切核酸酶）切割dL来增强反应。当修复被阻止时，聚合酶β是全细胞提取物中最具反应性的交联蛋白。通过“长补丁”（多核苷酸）BER途径处理损伤，在很大程度上避免了与dL的交联。然而，如果过度损伤导致DNA中未修复的氧化损伤的积累，则可能存在聚合酶β介导的交联形成的危险。了解细胞如何应对这种复杂的损伤是一个重要的问题。Ape 1蛋白除了在防御外源性物质引起的DNA损伤中发挥作用外，还对处理培养中生长的人类细胞中的内源性DNA损伤至关重要。使用RNA干扰技术抑制Ape 1导致各种细胞类型中的细胞增殖停滞和细胞凋亡激活，与未修复的脱碱基DNA损伤的积累相关。值得注意的是，所有这些作用都被不相关的S.酿酒酵母，其仅与Ape 1（AP内切核酸酶）共享酶修复功能。(c)2005 Elsevier B. V.保留所有权利。
Many oxidative DNA lesions are handled well by base excision repair (BER), but some types may be problematic. Recent work indicates that 2-deoxyribonolactone (dL) is such a lesion by forming stable, covalent cross-links between the abasic residue and DNA repair proteins with lyase activity. In the case of DNA polymerase beta, the reaction is potentiated by incision of dL by Ape1, the major mammalian AP endonuclease. When repair is prevented, polymerase beta is the most reactive cross-linking protein in whole-cell extracts. Cross-linking with dL is largely avoided by processing the damage through the "long-patch" (multinucleotide) BER pathway. However, if excess damage leads to the accumulation of unrepaired oxidative lesions in DNA, there may be a danger of polymerase beta-mediated cross-link formation. Understanding how cells respond to such complex damage is an important issue. In addition to its role in defending against DNA damage caused by exogenous agents, Ape 1 protein is essential for coping with the endogenous DNA damage in human cells grown in culture. Suppression of Ape1 using RNA-interference technology causes arrest of cell proliferation and activation of apoptosis in various cell types, correlated with the accumulation of unrepaired abasic DNA damage. Notably, all these effects are reversed by expression of the unrelated protein Apn1 of S. cerevisiae, which shares only the enzymatic repair function with Ape 1 (AP endonuclease). (c) 2005 Elsevier B.V. All rights reserved.