Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells

• Published in: Cell division Vol. 7; no. 1; p. 2
• Main Authors: Barra, Viviana, Schillaci, Tiziana, Lentini, Laura, Costa, Giuseppe, Di Leonardo, Aldo
• Format: Journal Article
• Language: English
• Published: England BioMed Central 03.02.2012; BioMed Central Ltd; BMC
• Subjects: Aneuploidy; Cancer; Cell cycle; Cell division; Cell growth; Cell proliferation; Centrosomes; Chromosomes; Colleges & universities; Cyclin-dependent kinase inhibitor p21; DNA damage; DNA methylation; DNMT1; Dnmt1 gene; DNMT1 protein; Epigenetics; Experiments; Fibroblasts; G1 arrest; Genomes; Genomic instability; p14ARF protein; p53 protein; Post-transcription; Real time; Spindles; Tumor cells; Tumors
• ISSN: 1747-1028; 1747-1028
• DOI: 10.1186/1747-1028-7-2

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.