DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis
DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis
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DOI：
10.1016/s0092-8674(03)00270-8
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发表时间：
2003-04-18
期刊：
影响因子：
64.5
通讯作者：
Mizrahi, V
中科院分区：
文献类型：
--
作者：
Boshoff, HIM;Reed, MB;Mizrahi, V
在一些生物体中，包括重要的病原体和共生体中，主要复制DNA聚合酶（DnaE）的多个拷贝的存在仍然是一个未解之谜。我们假设一个拷贝可能参与易错DNA修复合成。我们发现，紫外线照射结核分枝杆菌的结果增加突变频率的存活分数。我们确定dnaE2作为一个基因，在体外上调的几种DNA损伤剂，以及在感染小鼠。这种蛋白质的丢失降低了紫外线照射后芽孢杆菌的存活率和微生物在小鼠中的毒力。我们的数据表明，DnaE2，而不是易错DNA聚合酶的Y家族的成员，是通过诱导突变的生存的主要介质，可以直接导致体内耐药性的出现。这些结果可能表明一个潜在的新的治疗干预的目标。
The presence of multiple copies of the major replicative DNA polymerase (DnaE) in some organisms, including important pathogens and symbionts, has remained an unresolved enigma. We postulated that one copy might participate in error-prone DNA repair synthesis. We found that UV irradiation of Mycobacterium tuberculosis results in increased mutation frequency in the surviving fraction. We identified dnaE2 as a gene that is upregulated in vitro by several DNA damaging agents, as well as during infection of mice. Loss of this protein reduces both survival of the bacillus after UV irradiation and the virulence of the organism in mice. Our data suggest that DnaE2, and not a member of the Y family of error-prone DNA polymerases, is the primary mediator of survival through inducible mutagenesis and can contribute directly to the emergence of drug resistance in vivo. These results may indicate a potential new target for therapeutic intervention.