Xpf and not the Fanconi anaemia proteins or Rev3 accounts for the extreme resistance to cisplatin in Dictyostelium discoideum.
Xpf and not the Fanconi anaemia proteins or Rev3 accounts for the extreme resistance to cisplatin in Dictyostelium discoideum.
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DOI：
10.1371/journal.pgen.1000645
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发表时间：
2009-09
期刊：
影响因子：
4.5
通讯作者：
Patel KJ
中科院分区：
文献类型：
--
作者：
Zhang XY;Langenick J;Traynor D;Babu MM;Kay RR;Patel KJ
像盘状盘基骨菌这样的生物，通常被称为DNA损伤“极端微生物”，可以在暴露于极高剂量的辐射和DNA交联剂下存活。这些物质形成高毒性的DNA交联，造成广泛的DNA损伤。然而，对于盘基ostelium和其他“极端微生物”如何耐受和修复如此大量的DNA交联，人们知之甚少。在这里，我们描述了一个全面的遗传分析交联修复盘状盘齿骨。我们分析了在高等真核生物中对去除DNA交联的复制偶联修复过程至关重要的三个基因组：范可尼贫血途径（FA）、翻译合成（TLS）和核苷酸切除修复。基因破坏研究意外地揭示了FA基因和TLS酶Rev3在盘基骨菌对交联的耐受性中起次要作用。然而，Xpf核酸酶亚组分的破坏导致对交联的超敏反应。遗传相互作用研究表明，虽然Xpf与FA和TLS基因产物一起起作用，但大多数Xpf介导的修复是独立于这两个基因群的。这些结果表明Dictyostelium利用独特的Xpf核酸酶介导的修复过程来去除交联DNA。其他DNA抗损伤生物和化学耐药癌细胞可能采用类似的策略来产生对DNA交联剂的抗性。生物体不断暴露于环境和内源性分子中，这些分子会对其基因组中的DNA进行化学修饰。一种特别有害的化学修饰是当两条DNA链交联时。这些交联必须被移除，这样基因组才能被复制，而它们的持久性所造成的损害经常被用于癌症化疗。所有生物体都已经发展出有效的方法来去除这些损伤，这也不足为奇，在原核生物和真核生物中的研究表明，交联是通过某些DNA修复途径的协同作用来去除的。虽然积累交联的明显途径是暴露于抗癌药物，但这些损伤也可能在DNA中自发产生。这可能就是为什么一种交联修复途径的遗传失活导致人类灾难性疾病范可尼贫血的原因。在这里，我们确定了社会性变形虫盘基骨虫（Dictyostelium disideum）是如何去除交联的，这种生物对dna损伤剂具有不同寻常的抵抗力。我们的结果表明，这种生物已经进化出一种独特的策略来去除这些病变。更具体地说，我们发现一种特殊的核酸酶亚组分通过一种独特的修复过程去除交联。我们假设这种去除交联的策略可以被其他DNA抗损伤生物和已经对化疗产生耐药性的癌细胞使用。
Organisms like Dictyostelium discoideum, often referred to as DNA damage “extremophiles”, can survive exposure to extremely high doses of radiation and DNA crosslinking agents. These agents form highly toxic DNA crosslinks that cause extensive DNA damage. However, little is known about how Dictyostelium and the other “extremophiles” can tolerate and repair such large numbers of DNA crosslinks. Here we describe a comprehensive genetic analysis of crosslink repair in Dictyostelium discoideum. We analyse three gene groups that are crucial for a replication-coupled repair process that removes DNA crosslinks in higher eukarya: The Fanconi anaemia pathway (FA), translesion synthesis (TLS), and nucleotide excision repair. Gene disruption studies unexpectedly reveal that the FA genes and the TLS enzyme Rev3 play minor roles in tolerance to crosslinks in Dictyostelium. However, disruption of the Xpf nuclease subcomponent results in striking hypersensitivity to crosslinks. Genetic interaction studies reveal that although Xpf functions with FA and TLS gene products, most Xpf mediated repair is independent of these two gene groups. These results suggest that Dictyostelium utilises a distinct Xpf nuclease-mediated repair process to remove crosslinked DNA. Other DNA damage–resistant organisms and chemoresistant cancer cells might adopt a similar strategy to develop resistance to DNA crosslinking agents. Organisms are constantly exposed to environmental and endogenous molecules that chemically modify the DNA in their genomes. A particularly pernicious chemical modification is when the two strands of DNA are crosslinked. These crosslinks must be removed so that genomes can be copied, and the damage caused by their persistence is often exploited in cancer chemotherapy. It is also no surprise that all organisms have developed effective means to remove these lesions, and work in prokaryotes and eukaryotes has shown that crosslinks are removed by the concerted action of certain DNA repair pathways. Whilst the obvious route of accumulating crosslinks is by exposure to anti-cancer drugs, these lesions may also arise spontaneously in DNA. This could be why inherited inactivation of one of the crosslink repair pathways results in the catastrophic human illness Fanconi anaemia. Here we determine how the social amoeba Dictyostelium discoideum, an organism that is unusually resistant to DNA-damaging agents, removes crosslinks. Our results indicate that this organism has evolved a distinct strategy to remove these lesions. More specifically, we discover that a particular nuclease subcomponent removes the crosslinks by a distinct repair process. We postulate that this strategy to remove crosslinks could be used by other DNA damage–resistant organisms and also by cancer cells that have developed resistance to chemotherapy.