%0 Journal Article
%T Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells
%A Viviana Barra
%A Tiziana Schillaci
%A Laura Lentini
%A Giuseppe Costa
%A Aldo Di Leonardo
%J Cell Division
%D 2012
%I BioMed Central
%R 10.1186/1747-1028-7-2
%X 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.Genomic instability is a characteristic of the majority of human tumors and is considered a driving force for tumorigenesis. Various forms of genome instability have been described and characterized by an increased rate of a number of different genetic alterations [1,2]. Most cancers show a form that is called chromosomal instability (CIN), which refers to the high rate of numerical and structural chromosome changes found in cancer cells compared to normal cells. Numerical CIN is characterized by gains and losses of whole chromosomes (aneuploidy) during cell proliferation. Mutations in genes encoding mitotic regulators [3] and in genes controlling centrosome numbers and tumor suppressors [4-7] have been suggested as molecular defects underlying aneuploidy.Nevertheless, correct chromosome structure and function may play a role in the stabilization and normal functioning of chromosome segregation. Indeed, it is now accepted that gene expression and chromosome organization are mainly affected by epigenetic marks and may be implicated in the normal chromosome segregation process. Thus, epigenetic alterations should be considered
%K G1 arrest
%K aneuploidy
%K DNA methylation
%K DNMT1
%U http://www.celldiv.com/content/7/1/2