Parp1 localizes within the Dnmt1 promoter and protects its unmethylated state by its enzymatic activity.
Parp1 localizes within the Dnmt1 promoter and protects its unmethylated state by its enzymatic activity.
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Parp1 位于 Dnmt1 启动子内，并通过其酶活性保护其非甲基化状态。
DOI：
10.1371/journal.pone.0004717
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Caiafa, Paola
中科院分区：
文献类型：
--
作者：
Zampieri, Michele;Passananti, Claudio;Calabrese, Roberta;Perilli, Mariagrazia;Corbi, Nicoletta;De Cave, Fabiana;Guastafierro, Tiziana;Bacalini, Maria Giulia;Reale, Anna;Amicosante, Gianfranco;Calabrese, Lilia;Zlatanova, Jordanka;Caiafa, Paola
看家基因启动子中CpG岛的异常高甲基化和广泛存在的基因组低甲基化是发生在癌细胞中的典型事件。这些与癌症相关的DNA甲基化模式变化背后的分子机制尚不清楚。有两个问题特别重要：(I)如何在正常细胞中保护CpG岛免受甲基化，以及这种保护在癌细胞中是如何受到损害的，以及(Ii)癌细胞中全基因组去甲基化是如何发生的。后一个问题特别耐人寻味，因为到目前为止还没有发现DNA去甲基酶。我们的数据表明，在L929小鼠成纤维细胞中，由于异位过表达聚(ADP-核糖)糖水解酶(PARG)而导致ADP-核糖聚合物(PARS)的缺失，导致Dnmt1基因启动子中CpG岛的异常甲基化，进而关闭其转录。Dnmt1的转录沉默可能是基因组DNA普遍被动低甲基化的原因，我们在着丝粒周围重复序列的例子中检测到了这一现象。染色质免疫沉淀结果表明，在正常细胞中，DNMT1启动子被多聚(ADP-核糖基)PARP1占据，提示PARP1具有保护启动子免受甲基化的作用。总之，PARG过表达后的基因组甲基化模式反映了癌细胞的模式特征，支持了我们的观点，即PARP/ParG活性之间的正确平衡维持了正常细胞中的DNA甲基化模式。在正常细胞中，PARP1和ADP-核糖聚合物定位于Dnmt1启动子上，这增加了PARylated PARP1标记基因组中必须保持未甲基化的序列并保护它们免受甲基化的可能性，从而在基因表达的表观遗传调控中发挥作用。
Aberrant hypermethylation of CpG islands in housekeeping gene promoters and widespread genome hypomethylation are typical events occurring in cancer cells. The molecular mechanisms behind these cancer-related changes in DNA methylation patterns are not well understood. Two questions are particularly important: (i) how are CpG islands protected from methylation in normal cells, and how is this protection compromised in cancer cells, and (ii) how does the genome-wide demethylation in cancer cells occur. The latter question is especially intriguing since so far no DNA demethylase enzyme has been found. Our data show that the absence of ADP-ribose polymers (PARs), caused by ectopic over-expression of poly(ADP-ribose) glycohydrolase (PARG) in L929 mouse fibroblast cells leads to aberrant methylation of the CpG island in the promoter of the Dnmt1 gene, which in turn shuts down its transcription. The transcriptional silencing of Dnmt1 may be responsible for the widespread passive hypomethylation of genomic DNA which we detect on the example of pericentromeric repeat sequences. Chromatin immunoprecipitation results show that in normal cells the Dnmt1 promoter is occupied by poly(ADP-ribosyl)ated Parp1, suggesting that PARylated Parp1 plays a role in protecting the promoter from methylation. In conclusion, the genome methylation pattern following PARG over-expression mirrors the pattern characteristic of cancer cells, supporting our idea that the right balance between Parp/Parg activities maintains the DNA methylation patterns in normal cells. The finding that in normal cells Parp1 and ADP-ribose polymers localize on the Dnmt1 promoter raises the possibility that PARylated Parp1 marks those sequences in the genome that must remain unmethylated and protects them from methylation, thus playing a role in the epigenetic regulation of gene expression.
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DOI：
10.1074/jbc.m801170200
发表时间：
2008-08-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Guastafierro T;Cecchinelli B;Zampieri M;Reale A;Riggio G;Sthandier O;Zupi G;Calabrese L;Caiafa P
通讯作者：
Caiafa P
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
64.5
作者：
Kim, Tae Hoon;Abdullaev, Ziedulla K.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
14.9
作者：
Kimura, H;Nakamura, T;Shiota, K
通讯作者：
Shiota, K
影响因子：
64.8
作者：
Bell, AC;Felsenfeld, G
通讯作者：
Felsenfeld, G