DNA demethylation caused by 5-Aza-2'-deoxycytidine induces mitotic alterations and aneuploidy

Oncotarget
Giuseppe CostaAldo Di Leonardo

Abstract

Aneuploidy, the unbalanced number of chromosomes in a cell, is considered a prevalent form of genetic instability and is largely acknowledged as a condition implicated in tumorigenesis. Epigenetic alterations like DNA hypomethylation have been correlated with cancer initiation/progression. Furthermore, a growing body of evidence suggests the involvement of epigenome-wide disruption as a cause of global DNA hypomethylation in aneuploidy generation.Here, we report that the DNA hypomethylating drug 5-aza-2'-deoxycytidine (DAC), affects the correct ploidy of nearly diploid HCT-116 human cells by altering the methylation pattern of the chromosomes. Specifically, we show that a DAC-induced reduction of 5-Methyl Cytosine at the pericentromeric region of chromosomes correlates with aneuploidy and mitotic defects.Our results suggest that DNA hypomethylation leads to aneuploidy by altering the DNA methylation landscape at the centromere that is necessary to ensure proper chromosomes segregation by recruiting the proteins necessary to build up a functional kinetochore.

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Citations

Nov 30, 2018·Environmental and Molecular Mutagenesis·Yoon Hee ChoHai Won Chung
Sep 21, 2019·Nature Communications·Hyunchul JungJung Kyoon Choi
Jul 10, 2020·International Journal of Molecular Sciences·Raffaella MelfiAldo Di Leonardo
Jul 24, 2020·Genes·Danilo CilluffoAldo Di Leonardo
Apr 18, 2017·Epigenetics & Chromatin·Arlette RwigemeraGeraldine Delbes
Feb 2, 2021·International Journal of Pharmaceutics·Marina MassaroSerena Riela
Jun 5, 2021·Epigenetics & Chromatin·Xena Giada Pappalardo, Viviana Barra
Sep 30, 2021·The EMBO Journal·Mirjam A BeckChristian Seiser

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Methods Mentioned

BETA
Methylation Specific PCR
fluorescence microscopy
PCR
flow cytometry
profiler
Fluorescence
light microscopy
chromosomal aberrations
FACS
Assay

Software Mentioned

Adobe PhotoShop
Quantity One
modfit
ImageJ
Pro
Vision40 V
BLAST
Origin
OriginPro
Primer Express

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