Background: Aneuploidy is considered the result of chromosomesegregation errors caused by defects in the mitotic spindleassembly, centrosome duplication, cell-cycle checkpoints andepigenetic changes. Usually, aneuploidy affects negatively proliferationof normal cells. However, it is frequently associatedwith cancer that is characterized by a uncontrolled proliferation.Thus, understanding the pathway(s) that block proliferation ofaneuploid cells might open new avenue to exploit new cancertherapies.O bservations: We found that in primary human fi broblasts(IMR90) knocking down of DNMT1, a member of epigeneticmachinery is perceived by the cell as a stress signal that inducesp14ARF activation followed by TP53 stabilization that in turntransactivates p21waf1 triggering the G1 arrest. DNMT1 depletedcells bypassed the arrest and became aneuploid when TP53 orp14ARF were simultaneously silenced by RNAi. In addition byusing stable near-diploid human tumor cells (HCT116), whichare p14ARF-null and TP53-wt, we found that DNMT1 depletedHCT116 cells did not arrest in G1, underwent overall DNA demethylationand become aneuploid.C onclusions: Our results suggest that Dnmt1 depletion triggeredG1 arrest in human fi broblasts by activating a pathway p14ARF/TP53 dependent thus avoiding aneuploidy caused by DNA demethylationcoupled with incorrect cycle progression.
|Number of pages||1|
|Publication status||Published - 2011|