Formation of carcinogenic chromosomal rearrangements in human thyroid cells after induction of double-strand DNA breaks by restriction endonucleases.
Formation of carcinogenic chromosomal rearrangements in human thyroid cells after induction of double-strand DNA breaks by restriction endonucleases.
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DOI：
10.1530/erc-11-0314
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发表时间：
2012-06
影响因子：
3.9
通讯作者：
Nikiforov YE
中科院分区：
文献类型：
--
作者：
Evdokimova V;Gandhi M;Rayapureddi J;Stringer JR;Nikiforov YE
电离辐射（IR）暴露会增加甲状腺癌和其他癌症类型的风险。染色体重排，如RET/PTC，是辐射相关甲状腺癌的典型特征，可由体外辐射诱发。IR导致双链断裂（DSB），表明这种损伤导致RET/PTC，但重排机制尚未建立。为了研究其机制，我们探讨了通过电穿孔限制性内切酶（REs）到HTori-3人甲状腺细胞诱导RET/PTC的可能性。我们使用了五个RE，诱导DSB的剂量依赖性的方式与IR。虽然所有，但一个RE引起DSB在一个或多个涉及RET/PTC的三个基因，重排检测到只有在细胞电穿孔与PvuII（25和100 U）或StuI（100和250 U）。主要的重排类型是RET/PTC 3，这是人甲状腺癌的特征，发生在与甲状腺相关的放射性碘暴露后早期。产生RET/PTC的两种酶仅在两个融合伴侣基因之一中具有限制性位点。此外，产生RET/PTC的两种酶具有成簇存在的限制性位点，而不能诱导RET/PTC的RE则不是这种情况。总之，我们建立了RE诱导DSB的模型，并首次报告了RE产生的DSB导致致癌染色体重排的形成，主要是RET/PTC 3。我们的数据还提出了一种可能性，RET/PTC重排可以启动一个复杂的DSB，诱导在融合伴侣基因之一。
Ionizing radiation (IR) exposure increases the risk of thyroid cancer and other cancer types. Chromosomal rearrangements, such as RET/PTC, are characteristic features of radiation-associated thyroid cancer and can be induced by radiation in vitro. IR causes double-strand breaks (DSBs), suggesting that such damage leads to RET/PTC, but the rearrangement mechanism has not been established. To study the mechanism, we explored the possibility of inducing RET/PTC by electroporation of restriction endonucleases (REs) into HTori-3 human thyroid cells. We used five REs, which induced DSB in a dose-dependent manner similar to that seen with IR. Although all but one RE caused DSB in one or more of the three genes involved in RET/PTC, rearrangement was detected only in cells electroporated with either PvuII (25 and 100 U) or StuI (100 and 250 U). The predominant rearrangement type was RET/PTC3, which is characteristic of human thyroid cancer arising early after Chernobyl-related radioactive iodine exposure. Both enzymes that produced RET/PTC had restriction sites only in one of the two fusion partner genes. Moreover, the two enzymes that produced RET/PTC had restriction sites present in clusters, which was not the case for RE that failed to induce RET/PTC. In summary, we establish a model of DSB induction by RE and report for the first time the formation of carcinogenic chromosomal rearrangements, predominantly RET/PTC3, as a result of DSB produced by RE. Our data also raise a possibility that RET/PTC rearrangement can be initiated by a complex DSB that is induced in one of the fusion partner genes.
由限制性核酸内切酶引起的DNA双链断裂引起的鼠C3H 10T1/2细胞的致癌转化。
影响因子：
8.8
作者：
Bryant, P E;Riches, A C
通讯作者：
Riches, A C