Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia.
Base excision repair of chemotherapeutically-induced alkylated DNA damage predominantly causes contractions of expanded GAA repeats associated with Friedreich's ataxia.
复制标题
DOI：
10.1371/journal.pone.0093464
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Lai Y;Beaver JM;Lorente K;Melo J;Ramjagsingh S;Agoulnik IU;Zhang Z;Liu Y
共济失调蛋白基因第一内含子内GAA·TTC重复序列的扩增是弗里德赖希共济失调（FRDA）的原因，FRDA是一种常染色体隐性遗传性神经退行性疾病。然而，迄今为止尚未开发出有效的治疗方法。在这项研究中，我们探讨了通过化疗诱导的DNA碱基损伤和随后的碱基切除修复（BER）缩短与FRDA相关的扩展GAA重复序列的可能性。我们提供了第一个证据，烷基化的DNA损伤诱导的替莫唑胺，化疗DNA损伤剂可以诱导大量的GAA重复收缩/删除，但只有有限的扩展在FRDA患者的淋巴母细胞。我们发现替莫唑胺诱导的GAA重复序列不稳定性是由BER介导的。在（GAA）20个重复序列的背景下，对无碱基位点的BER的进一步表征表明，病变主要导致8个重复序列的大缺失沿着小扩增。这是因为替莫唑胺诱导的单链断裂最初导致DNA滑移，并在受损链的上游区域形成小的GAA重复环和在模板链上形成小的TTC环。这允许有限的pol β DNA合成和形成被FEN 1切割的短的5 '-GAA重复侧翼，从而导致小的重复扩增。在BER的后期阶段，小模板环扩展成大模板环，导致形成长的5 '-GAA重复瓣。然后Pol β进行有限的DNA合成以绕过环，并且FEN 1去除长重复瓣，最终导致大重复缺失。我们的研究表明，化疗诱导的烷基化DNA损伤可以通过BER在FRDA患者细胞中诱导扩增的GAA重复序列的大收缩/缺失。这进一步表明开发化疗烷化剂以缩短用于治疗FRDA的扩展的GAA重复序列的潜力。
Expansion of GAA·TTC repeats within the first intron of the frataxin gene is the cause of Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative disorder. However, no effective treatment for the disease has been developed as yet. In this study, we explored a possibility of shortening expanded GAA repeats associated with FRDA through chemotherapeutically-induced DNA base lesions and subsequent base excision repair (BER). We provide the first evidence that alkylated DNA damage induced by temozolomide, a chemotherapeutic DNA damaging agent can induce massive GAA repeat contractions/deletions, but only limited expansions in FRDA patient lymphoblasts. We showed that temozolomide-induced GAA repeat instability was mediated by BER. Further characterization of BER of an abasic site in the context of (GAA)20 repeats indicates that the lesion mainly resulted in a large deletion of 8 repeats along with small expansions. This was because temozolomide-induced single-stranded breaks initially led to DNA slippage and the formation of a small GAA repeat loop in the upstream region of the damaged strand and a small TTC loop on the template strand. This allowed limited pol β DNA synthesis and the formation of a short 5'-GAA repeat flap that was cleaved by FEN1, thereby leading to small repeat expansions. At a later stage of BER, the small template loop expanded into a large template loop that resulted in the formation of a long 5'-GAA repeat flap. Pol β then performed limited DNA synthesis to bypass the loop, and FEN1 removed the long repeat flap ultimately causing a large repeat deletion. Our study indicates that chemotherapeutically-induced alkylated DNA damage can induce large contractions/deletions of expanded GAA repeats through BER in FRDA patient cells. This further suggests the potential of developing chemotherapeutic alkylating agents to shorten expanded GAA repeats for treatment of FRDA.
登录
查看更多内容
影响因子：
4.7
作者：
Gottesfeld JM;Rusche JR;Pandolfo M
通讯作者：
Pandolfo M
影响因子：
3.7
作者：
De Biase, Irene;Chutake, Yogesh K.;Bidichandani, Sanjay I.
通讯作者：
Bidichandani, Sanjay I.
影响因子：
158.5
作者：
Durr, A;Cossee, M;Koenig, M
通讯作者：
Koenig, M
影响因子：
4.4
作者：
De Biase, Irene;Rasmussen, Astrid;Bidichandani, Saniav I.
通讯作者：
Bidichandani, Saniav I.
影响因子：
14.9
作者：
Grabczyk, Ed;Mancuso, Miriam;Sammarco, Mimi C.
通讯作者：
Sammarco, Mimi C.