Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?
Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?
复制标题
DOI：
10.1158/1078-0432.ccr-10-2044
复制
发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Yegnasubramanian S
中科院分区：
文献类型：
--
作者：
Haffner MC;De Marzo AM;Meeker AK;Nelson WG;Yegnasubramanian S
一种新兴的转录激活模型表明，转录程序的诱导，例如分别用雄激素或雌激素刺激前列腺或乳腺细胞，涉及DNA损伤的形成，包括双链断裂(DSB)、DSB修复蛋白的募集以及新激活的基因向转录中心的移动。 DSB 可以由 II 类拓扑异构酶 TOP2B 介导，该酶与雄激素受体 (AR) 和雌激素受体 (ER) 一起募集到靶基因上的调节位点，并且显然是这些基因的有效转录激活所必需的。这些 DSB 被 DNA 修复机制识别，从而触发 PARP1、ATM 和 DNA-PK 等修复蛋白的募集。如果被非法修复，这种 DSB 可能会引发基因组重排的形成，例如前列腺癌中的 TMPRSS2-ERG 融合癌基因。在这里，我们假设这些转录诱导的 TOP2B 介导的 DSB 也可以用于治疗，并提出，在乳腺癌和前列腺癌等激素依赖性肿瘤中，激素循环疗法与拓扑异构酶 II 毒物或 DNA 修复成分 PARP1 和 DNA-PK 抑制剂相结合，可以压倒具有转录相关双链断裂的癌细胞。这种策略可能在前列腺癌等增殖率较低的癌症中特别有用，而其他针对快速增殖细胞的化疗策略的成功却有限。
An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor (AR) and estrogen receptor (ER) to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSB are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as PARP1, ATM and DNA-PK. If illegitimately repaired, such DSB can seed the formation of genomic rearrangements like the TMPRSS2-ERG fusion oncogene in prostate cancer. Here we hypothesize that these transcription induced TOP2B mediated DSB can also be exploited therapeutically and propose that, in hormone dependent tumors like breast and prostate cancers, a hormone cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated double strand breaks. Such strategies may find particular utility in cancers, like prostate cancer, that show low proliferation rates, where other chemotherapeutic strategies that target rapidly proliferating cells have had limited success.