0000000001077204
AUTHOR
V Barra
Bypass of G1 arrest induced by DNMT1 posttranscriptional silencing triggers aneuploidy in human cells.
Aneuploidy is a major source of genomic instability in cancer, resulting from chromosome segregation errors caused by defects in genes controlling correct mitotic spindle assembly, centrosome duplication and cell cycle checkpoints. Interestingly in aneuploid cells some of these genes, although not mutated, were underexpressed suggesting the involvement of epigenetic alterations. DNA methylation and histone modifications are the main epigenetic modifications occurring in cells. DNA methyl-transferase 1 (Dnmt1) is known to restore DNA methylation patterns during cell divisions. We investigated the effects of DNMT1 silencing by RNA-interference on the generation of aneuploidy in primary human …
Identification of mechanism(s) leading to hyperdiploidy in progenitor tumor cells derived from MCF7 breast cancer cells
Stem cells are a minor population of mostly resting cells defined by their long life, high clonogenicity, self-replicating potential, plasticity, and drug resistance (Finn, 2008). Cells with these properties have been identified in various normal and cancerous human tissues (Wicha, 2006), as well as in several long-term tumor cell lines (Setoguchi, 2004). We have some preliminary data indicating that cells isolated from MCF7 line divide slowly and form spheres, both features of progenitors tumor cells, when grown in ultralow adherent plates and in absence of serum. Furthermore, these features were associated to two distinct populations characterized by different content in terms of number o…
DNMT1 depletion activates a pathway p14ARF/TP53 controlled that induces G1 arrest preventing DNA demethylation and aneuploidy
Background: Aneuploidy is considered the result of chromosome segregation errors caused by defects in the mitotic spindle assembly, centrosome duplication, cell-cycle checkpoints and epigenetic changes. Usually, aneuploidy affects negatively proliferation of normal cells. However, it is frequently associated with cancer that is characterized by a uncontrolled proliferation. Thus, understanding the pathway(s) that block proliferation of aneuploid cells might open new avenue to exploit new cancer therapies. O bservations: We found that in primary human fi broblasts (IMR90) knocking down of DNMT1, a member of epigenetic machinery is perceived by the cell as a stress signal that induces p14ARF …