Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells.
Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells.
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DOI：
10.1186/1747-1028-7-2
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发表时间：
2012-02-03
期刊：
影响因子：
2.3
通讯作者：
Di Leonardo A
中科院分区：
文献类型：
--
作者：
Barra V;Schillaci T;Lentini L;Costa G;Di Leonardo A
非整倍性被认为是癌症基因组不稳定的主要来源，它通常被认为是染色体分离错误的结果，包括控制有丝分裂纺锤体组装、中心体复制和细胞周期检查点的基因缺陷。非整倍体和染色体不稳定性也与表观遗传改变相关，然而这种相关性的分子基础尚不清楚。为了解决表观遗传变化和非整倍体之间存在的功能联系，我们使用rna干扰来沉默DNMT1基因，该基因编码DNA甲基转移酶的一个高度保守的成员。DNMT1缺失减缓了近二倍体人肿瘤细胞（HCT116）的增殖，并通过诱导p53稳定和p21waf1反激活，在原代人成纤维细胞（IMR90）中触发G1阻滞。值得注意的是，p53的增加不是由DNA损伤引起的，也不是在p14-ARF转录后沉默后观察到的。有趣的是，DNMT1沉默的p53或p14-ARF耗尽的细胞在G1期没有停止，而是经历了DNA低甲基化并成为非整倍体。我们的研究结果表明，DNMT1缺失触发p14ARF/p53依赖的细胞周期阻滞，以抵消DNA甲基化变化引起的非整倍体。
Aneuploidy has been acknowledged as a major source of genomic instability in cancer, and it is often considered the result of chromosome segregation errors including those caused by defects in genes controlling the mitotic spindle assembly, centrosome duplication and cell-cycle checkpoints. Aneuploidy and chromosomal instability has been also correlated with epigenetic alteration, however the molecular basis of this correlation is poorly understood. To address the functional connection existing between epigenetic changes and aneuploidy, we used RNA-interference to silence the DNMT1 gene, encoding for a highly conserved member of the DNA methyl-transferases. DNMT1 depletion slowed down proliferation of near-diploid human tumor cells (HCT116) and triggered G1 arrest in primary human fibroblasts (IMR90), by inducing p53 stabilization and, in turn, p21waf1 transactivation. Remarkably, p53 increase was not caused by DNA damage and was not observed after p14-ARF post-transcriptional silencing. Interestingly, DNMT1 silenced cells with p53 or p14-ARF depleted did not arrest in G1 but, instead, underwent DNA hypomethylation and became aneuploid. Our results suggest that DNMT1 depletion triggers a p14ARF/p53 dependent cell cycle arrest to counteract the aneuploidy induced by changes in DNA methylation.
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影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
DOI：
10.1073/pnas.032479999
发表时间：
2002-02-19
影响因子：
11.1
作者：
Lingle, WL;Barrett, SL;Salisbury, JL
通讯作者：
Salisbury, JL
影响因子：
8
作者：
James, S. R.;Link, P. A.;Karpf, A. R.
通讯作者：
Karpf, A. R.
影响因子：
7.7
作者：
Easwaran, HP;Schermelleh, L;Cardoso, MC
通讯作者：
Cardoso, MC
影响因子：
4.8
作者：
Lentini, L;Pipitone, L;Di Leonardo, A
通讯作者：
Di Leonardo, A