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 fibroblasts (IMR90) and stable near-diploid human tumor cells (HCT116). Dnmt1 depletion induced aneuploidy in addition to cell proliferation delay in HCT116 cells and transient G1 arrest in IMR90 cells. IMR90-siDNTM1 cells showed increased levels of the TP53 tumor suppressor. Moreover, cells where DNMT1 and TP53 were simultaneously silenced entered the cell cycle, suggesting TP53 as likely responsible for the observed G1 arrest. DNMT1 downregulation was also associated to global DNA demethylation in HCT116 cells and to partially decondensed pericentromeric chromatin in IMR90 cells. Our results suggest that Dnmt1 depletion triggers a cell cycle arrest pathway mediated by TP53 in IMR90 cells, whose dysfunction induces aneuploidy likely affecting the correct chromosome segregation by altering pericentromeric structure.

Barra, V., Lentini, L., Di Leonardo, A. (2010). Bypass of G1 arrest induced by DNMT1 posttranscriptional silencing triggers aneuploidy in human cells.. In Atti del VIII congresso annuale del Dipartimento di Biologia Cellulare e dello Sviluppo “A. Monroy” 2010.

Bypass of G1 arrest induced by DNMT1 posttranscriptional silencing triggers aneuploidy in human cells.

Barra, V;LENTINI, Laura;DI LEONARDO, Aldo
2010-01-01

Abstract

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 fibroblasts (IMR90) and stable near-diploid human tumor cells (HCT116). Dnmt1 depletion induced aneuploidy in addition to cell proliferation delay in HCT116 cells and transient G1 arrest in IMR90 cells. IMR90-siDNTM1 cells showed increased levels of the TP53 tumor suppressor. Moreover, cells where DNMT1 and TP53 were simultaneously silenced entered the cell cycle, suggesting TP53 as likely responsible for the observed G1 arrest. DNMT1 downregulation was also associated to global DNA demethylation in HCT116 cells and to partially decondensed pericentromeric chromatin in IMR90 cells. Our results suggest that Dnmt1 depletion triggers a cell cycle arrest pathway mediated by TP53 in IMR90 cells, whose dysfunction induces aneuploidy likely affecting the correct chromosome segregation by altering pericentromeric structure.
dic-2010
CONGRESSO ANNUALE DEL DIPARTIMENTO DI BIOLOGIA CELLULARE E DELLO SVILUPPO “A.MONROY”
Palermo (Italy),
20-21 Dicembre 2010
VIII
2010
38
Barra, V., Lentini, L., Di Leonardo, A. (2010). Bypass of G1 arrest induced by DNMT1 posttranscriptional silencing triggers aneuploidy in human cells.. In Atti del VIII congresso annuale del Dipartimento di Biologia Cellulare e dello Sviluppo “A. Monroy” 2010.
Proceedings (atti dei congressi)
Barra, V; Lentini, L; Di Leonardo, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/60020
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