The regulation of chromatin structure is a dynamic and complex process that is modulated by epigenetic mechanisms. Malfunctioning of these processes cancause gene expression alteration and could compromise important events such as chromosome condensation and segregation. Imbalance in cytosine methylation andderegulation of DNA-methyltransferases (DNMTs), and of DNMT1 in particular, is frequent in human cancers.To investigate DNMT1 implication in the generation of aneuploidy we evaluated the effects of its depletion by RNA-interference both in primary human cells (IMR90)and in near diploid human tumor (HCT116) cells. Posttranscriptional silencing of DNMT1 induced aneuploidy, cell proliferation delay and cell cycle arrest in HCT116 cells and in IMR90 cells respectively. Thecell cycle arrest was transient because cells re-entered the cycle after that the effects of siRNAs targeting DNMT1 ended. Cells missing DNMT1 showedincreased levels of the p53 tumor suppressor gene thatcould be responsible for the observed cell cycle arrest.In fact when DNMT1 and p53 were simultaneouslysilenced cells did not arrest. Finally DNMT1 depletionwas associated to global DNA demethylation in tumorcells and to partially decondensed pericentromericchromatin in IMR90 cells. Our results suggest thatDNMT1 loss induces cell aneuploidy, probably byaffecting the correct chromosome segregation alteringpericentromeric structure by demethylation, and itactivates a cell cycle arrest pathway p53 mediated inIMR90 cells.
|Numero di pagine||1|
|Stato di pubblicazione||Published - 2009|