RESUMEN
Chromosome segregation during mitosis is monitored by the mitotic checkpoint and is dependent upon DNA methylation. ZBTB4 is a mammalian epigenetic regulator with high affinity for methylated CpGs that localizes at pericentromeric heterochromatin and is frequently downregulated in cancer. Here, we report that decreased ZBTB4 expression correlates with high genome instability across many frequent human cancers. In human cell lines, ZBTB4 depletion was sufficient to increase the prevalence of micronuclei and binucleated cells in parallel with aberrant mitotic checkpoint gene expression, a weakened mitotic checkpoint, and an increased frequency of lagging chromosomes during mitosis. To extend these findings, we generated Zbtb4-deficient mice. Zbtb4-/- mice were smaller than their wild-type littermates. Primary cells isolated from Zbtb4-/- mice exhibited diminished mitotic checkpoint activity, increased mitotic defects, aneuploid cells marked by a specific transcriptional signature, and increased genomic instability. Zbtb4-/- mice were also more susceptible to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA)-induced skin carcinogenesis. Our results establish the epigenetic regulator ZBTB4 as an essential component in maintaining genomic stability in mammals. Cancer Res; 77(1); 62-73. ©2016 AACR.
Asunto(s)
Aneuploidia , Transformación Celular Neoplásica/genética , Inestabilidad Genómica/genética , Puntos de Control de la Fase M del Ciclo Celular/genética , Neoplasias/genética , Proteínas Represoras/genética , Animales , Western Blotting , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Hibridación Fluorescente in Situ , Ratones , Ratones Noqueados , Microscopía Confocal , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Cutáneas/genéticaRESUMEN
DNA methylation compacts chromatin structure and represses gene transcription. It is important for numerous cellular processes, including embryonic development, X-chromosome inactivation, suppression of transposable elements, and cellular differentiation. In addition, environmental cues, including drugs, pollutants, trauma or early-life social environment, alter DNA methylation patterns in different organs. For instance, studies have unravelled a complex and dynamic interplay between environment, DNA methylation and neuron function during development and in the adult. This crosstalk is hypothesized as an essential molecular event underlying the effects of long-term memory, drug addiction, and several psychotic and behavioural disorders. In this review, we give a summary of this exciting field of research and highlight the molecular functions of DNA methylation and of proteins interacting with methylated DNA.