Histone methyltransferase DOT1L drives recovery of gene expression after a genotoxic attack.
Histone methyltransferase DOT1L drives recovery of gene expression after a genotoxic attack.
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DOI：
10.1371/journal.pgen.1003611
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Coin F
中科院分区：
文献类型：
--
作者：
Oksenych V;Zhovmer A;Ziani S;Mari PO;Eberova J;Nardo T;Stefanini M;Giglia-Mari G;Egly JM;Coin F
UV诱导的DNA损伤导致RNA合成的抑制。在去除DNA损伤后，转录恢复通过一个尚不清楚的过程进行。在这里，我们表明，敲除小鼠胚胎成纤维细胞（MEFDOT1L）中的组蛋白甲基转移酶DOT1L导致UV超敏反应耦合到UV照射后的转录起始恢复不足。然而，DOT 1L并不参与通过核苷酸切除修复途径消除紫外线诱导的DNA损伤。使用FRAP和ChIP实验，我们建立了DOT1L促进UV抑制基因的启动子上的前起始复合物的形成和转录活性染色质标记的出现。用曲古抑菌素A处理，松弛染色质，恢复转录起始和UV存活。我们的数据表明，DOT1L确保了一个开放的染色质结构，以重新激活RNA Pol II转录启动后的遗传毒性攻击。通过基因组DNA结构的变形，紫外线诱导的DNA损伤对包括复制和转录在内的各种核过程具有抑制作用。事实上，去除这些病变是细胞的优先事项，并且以暂停基本细胞过程以规避可能导致癌症的突变风险为代价。转录抑制和恢复的分子机制还不清楚，似乎比预期的更复杂。在这里，我们分析了紫外线照射后的转录恢复过程，发现它依赖于DOT1L，组蛋白甲基转移酶，促进紫外线抑制基因启动子处的转录机制的重组。我们的发现表明，基因毒性攻击后的转录恢复是染色质重塑酶控制下的一个活跃过程。
UV-induced DNA damage causes repression of RNA synthesis. Following the removal of DNA lesions, transcription recovery operates through a process that is not understood yet. Here we show that knocking-out of the histone methyltransferase DOT1L in mouse embryonic fibroblasts (MEFDOT1L) leads to a UV hypersensitivity coupled to a deficient recovery of transcription initiation after UV irradiation. However, DOT1L is not implicated in the removal of the UV-induced DNA damage by the nucleotide excision repair pathway. Using FRAP and ChIP experiments we established that DOT1L promotes the formation of the pre-initiation complex on the promoters of UV-repressed genes and the appearance of transcriptionally active chromatin marks. Treatment with Trichostatin A, relaxing chromatin, recovers both transcription initiation and UV-survival. Our data suggest that DOT1L secures an open chromatin structure in order to reactivate RNA Pol II transcription initiation after a genotoxic attack. Through the deformation of the genomic DNA structure, UV-induced DNA lesions have repressive effect on various nuclear processes including replication and transcription. As a matter of fact, the removal of these lesions is a priority for the cell and takes place at the expense of fundamental cellular processes that are paused to circumvent the risks of mutations that may lead to cancer. The molecular mechanism underlying transcription inhibition and recovery is not clearly understood and appears more complicated than anticipated. Here we analyzed the process of transcription recovery after UV-irradiation and found that it depends on DOT1L, a histone methyltransferase that promotes the reformation of the transcription machinery at the promoters of UV-repressed genes. Our discovery shows that transcription recovery after a genotoxic attack is an active process under the control of chromatin remodelling enzymes.
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影响因子：
3.8
作者：
Bostelman, Lindsey J.;Keller, Andrew M.;Thompson, Jeffrey S.
通讯作者：
Thompson, Jeffrey S.
影响因子：
5.3
作者：
Citterio, E;Van Den Boom, V;Vermeulen, W
通讯作者：
Vermeulen, W
影响因子：
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作者：
Feng, Q;Wang, HB;Zhang, Y
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TTDA与TFIIH的动态相互作用通过活细胞中的核苷酸切除修复稳定。
影响因子：
9.8
作者：
Giglia-Mari G;Miquel C;Theil AF;Mari PO;Hoogstraten D;Ng JM;Dinant C;Hoeijmakers JH;Vermeulen W
通讯作者：
Vermeulen W
影响因子：
4.7
作者：
CARREAU, M;EVENO, E;MEZZINA, M
通讯作者：
MEZZINA, M