Decarbamoyl mitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction.
Decarbamoyl mitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction.
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DOI：
10.1080/15384101.2014.997517
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发表时间：
2015
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影响因子：
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通讯作者：
Bargonetti J
中科院分区：
文献类型：
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作者：
Xiao G;Kue P;Bhosle R;Bargonetti J
链间交联诱导DNA复制叉停滞，这反过来激活核染色质上的ATR依赖性检查点和DNA修复。丝裂霉素C（MC）和十氨甲酰丝裂霉素C（DMC）诱导不同类型的DNA交联，DMC是一种更具细胞毒性的药物。我们先前报道了新型DMC诱导的β-链间DNA交联诱导p53非依赖性形式的细胞死亡。p53非依赖性DMC细胞毒性与Chk 1的激活和随后的耗竭有关。在这项研究中，我们进一步剖析了新的DMC信号转导途径，并询问它如何影响染色质相关蛋白。我们发现，DMC，而不是MC的治疗，刺激ATR从染色质和重新定位到细胞质的ATR的解离。ATR的染色质驱逐与核Rad 51灶的形成和Chk 1的磷酸化相结合。此外，DMC而不是MC激活gadd 45 α mRNA的表达。重要的是，通过shRNA敲低p53并不抑制DMC诱导的ATR与染色质的解离或减少gadd 45 α的转录激活。我们的研究结果表明，DMC诱导p53-独立的ATR从染色质中解离，促进Chk 1检查点激活和Rad 51染色质募集。我们的研究结果提供的证据表明，ATR染色质驱逐在乳腺癌细胞中是一个研究领域，应该集中在诱导p53非依赖性细胞死亡。
Interstrand crosslinks induce DNA replication fork stalling that in turn activates the ATR-dependent checkpoint and DNA repair on nuclear chromatin. Mitomycin C (MC) and Decarbamoyl Mitomycin C (DMC) induce different types of DNA crosslinks with DMC being a more cytotoxic agent. We previously reported that the novel DMC induced β–interstrand DNA crosslinks induce a p53-independent form of cell death. The p53-independent DMC cytotoxicity associates with the activation, and subsequent depletion, of Chk1. In this study we further dissect the novel DMC signal transduction pathway and asked how it influences chromatin-associated proteins. We found that treatment with DMC, but not MC, stimulated the disassociation of ATR from chromatin and re-localization of ATR to the cytoplasm. The chromatin eviction of ATR was coupled with the formation of nuclear Rad51 foci and the phosphorylation of Chk1. Furthermore, DMC but not MC, activated expression of gadd45α mRNA. Importantly, knocking down p53 via shRNA did not inhibit the DMC-induced disassociation of ATR from chromatin or reduce the activation of transcription of gadd45α. Our results suggest that DMC induces a p53-independent disassociation of ATR from chromatin that facilitates Chk1 checkpoint activation and Rad51 chromatin recruitment. Our findings provide evidence that ATR chromatin eviction in breast cancer cells is an area of study that should be focused on for inducing p53-independent cell death.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
DOI：
10.1073/pnas.96.5.1921
发表时间：
1999-03-02
影响因子：
11.1
作者：
Raderschall, E;Golub, EI;Haaf, T
通讯作者：
Haaf, T
影响因子：
5.3
作者：
Jiang, GC;Sancar, A
通讯作者：
Sancar, A
影响因子：
3.7
作者：
Brown AD;Sager BW;Gorthi A;Tonapi SS;Brown EJ;Bishop AJ
通讯作者：
Bishop AJ
DOI：
10.1038/nrc3088
发表时间：
2011-06-24
期刊：
Nature reviews. Cancer
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作者：
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