Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.
Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.
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DOI：
10.1021/tx200031q
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发表时间：
2011-05-16
影响因子：
4.1
通讯作者：
Pegg AE
中科院分区：
文献类型：
--
作者：
Pegg AE
O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）是一种广泛分布的独特的DNA修复蛋白，其作为单一试剂直接从DNA中去除位于鸟嘌呤O 6-位上的烷基，一步恢复DNA。这种蛋白质只起一次作用，其烷基化形式迅速降解。它是抵消包括N-亚硝基化合物和许多癌症化疗药物在内的形成此类加合物的试剂的致突变、致癌和细胞毒性作用的主要因素。本文综述了AGTs的结构、功能和作用机制，以及一个家族的相关烷基转移酶样蛋白，它不单独作用于修复DNA中的O 6-烷基鸟嘌呤，而是将修复与其他途径联系起来。还描述了AGTs通过形成AGT-DNA交联来刺激二卤代烷和其他双亲电体的DNA损伤能力的矛盾能力。AGTs的其他重要特性包括能够提供癌症治疗的烷化剂和AGT抑制剂，如O 6-苄基鸟嘌呤，可能克服这种阻力的可用性进行了讨论。最后，概述了AGT序列与其他蛋白质连接的融合蛋白的性质。这些蛋白质天然存在，并且被工程化以与O 6-苄基鸟嘌呤的衍生物特异性反应的合成变体是用特异性试剂标记蛋白质的有价值的研究技术的基础。
O6-Alkylguanine-DNA alkyltransferase (AGT) is a widely distributed, unique DNA repair protein that acts as a single agent to directly remove alkyl groups located on the O6-position of guanine from DNA restoring the DNA in one step. The protein acts only once and its alkylated form is degraded rapidly. It is a major factor in counteracting the mutagenic, carcinogenic and cytotoxic effects of agents that form such adducts including N-nitroso-compounds and a number of cancer chemotherapeutics. This review describes the structure, function and mechanism of action of AGTs and of a family of related alkyltransferase-like proteins, which do not alone act to repair O6-alkylguanines in DNA but link repair to other pathways. The paradoxical ability of AGTs to stimulate the DNA-damaging ability of dihaloalkanes and other bis-electrophiles via the formation of AGT-DNA crosslinks is also described. Other important properties of AGTs include the ability to provide resistance to cancer therapeutic alkylating agents and the availability of AGT inhibitors such as O6-benzylguanine that might overcome this resistance is discussed. Finally, the properties of fusion proteins in which AGT sequences are linked to other proteins are outlined. Such proteins occur naturally and synthetic variants engineered to react specifically with derivatives of O6-benzylguanine are the basis of a valuable research technique for tagging proteins with specific reagents.