A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage
A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage
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DOI：
10.1038/nature08444
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发表时间：
2009-10-01
期刊：
影响因子：
64.8
通讯作者：
Caldecott, Keith W.
中科院分区：
文献类型：
--
作者：
Ledesma, Felipe Cortes;El Khamisy, Sherif F.;Caldecott, Keith W.
拓扑异构酶调节DNA拓扑结构，是染色体代谢的许多方面的基础（1，2）。其活性涉及DNA的瞬时切割，如果其发生在内源性DNA损伤位点附近或存在拓扑异构酶毒物的情况下，则可导致拓扑异构酶诱导的DNA链断裂失败（3-5）。这些断裂的特征是酶通过3 '-或5'-磷酸酪氨酰键与DNA末端共价连接，并与遗传性人类疾病（6-8）、染色体不稳定性和癌症（4，9）有关，是一类重要的抗肿瘤毒药临床疗效的基础（3，9，10）。在含有酪氨酰-DNA磷酸二酯酶1（TDP 1）（一种切割3 '-磷酸酪氨酰键的酶）突变的个体中观察到的进行性神经退行性疾病说明了从捕获的拓扑异构酶中释放DNA末端的重要性（6-8）。然而，尽管含有这种末端的DNA双链断裂对染色体不稳定性和癌症的影响，但尚未报道切割5 '-磷酸酪氨酰键的互补人类酶（6-8）。在这里，我们确定了这样的酶在人类细胞中，并表明，这种活动有效地恢复5 '-磷酸末端在DNA双链断裂准备DNA连接。这种酶TTRAP是磷酸二酯酶的Mg 2 +/Mn 2+依赖性家族的成员。TTRAP的细胞耗竭导致对拓扑异构酶II诱导的DNA双链断裂的易感性和敏感性增加。据我们所知，TTRAP是第一个被鉴定的人5 '-酪氨酰DNA磷酸二酯酶，我们建议将这种酶命名为酪氨酰DNA磷酸二酯酶-2（TDP 2）。
Topoisomerases regulate DNA topology and are fundamental to many aspects of chromosome metabolism(1,2). Their activity involves the transient cleavage of DNA, which, if it occurs near sites of endogenous DNA damage or in the presence of topoisomerase poisons, can result in abortive topoisomerase-induced DNA strand breaks(3-5). These breaks feature covalent linkage of the enzyme to the DNA termini by a 3'- or 5'-phosphotyrosyl bond and are implicated in hereditary human disease(6-8), chromosomal instability and cancer(4,9), and underlie the clinical efficacy of an important class of anti-tumour poisons(3,9,10). The importance of liberating DNA termini from trapped topoisomerase is illustrated by the progressive neurodegenerative disease observed in individuals containing a mutation in tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that cleaves 3'-phosphotyrosyl bonds(6-8). However, a complementary human enzyme that cleaves 5'-phosphotyrosyl bonds has not been reported, despite the effect of DNA double-strand breaks containing such termini on chromosome instability and cancer(6-8). Here we identify such an enzyme in human cells and show that this activity efficiently restores 5'-phosphate termini at DNA double-strand breaks in preparation for DNA ligation. This enzyme, TTRAP, is a member of the Mg2+/Mn2+-dependent family of phosphodiesterases. Cellular depletion of TTRAP results in increased susceptibility and sensitivity to topoisomerase-II-induced DNA double-strand breaks. TTRAP is, to our knowledge, the first human 5'-tyrosyl DNA phosphodiesterase to be identified, and we suggest that this enzyme is denoted tyrosyl DNA phosphodiesterase-2 (TDP2).