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Heterochromatin HIstone Methylation Regulates Genome Stability

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Cancer is typically considered a genetic disease where gene deletions or mutations are responsible for cancer-promoting changes within the cell. However, deregulation of epigenetic mechanisms is also prevalent in a variety of cancer contexts, and is increasingly appreciated as a contributing factor in tumorigenesis. Epigenetic modifiers regulate the placement and removal of covalent modifications on histones to orchestrate the recruitment of effector proteins and influence the compaction and accessibility of chromatin. In this way, deregulation of histone modifying enzymes can have dramatic consequences for gene expression and chromatin architecture. Epigenetic marks of constitutive heterochromatin are both increased and decreased in different subsets of cancers. However, while previous studies have demonstrated that loss of methylation that marks constitutive heterochromatin compromises genomic stability the impact of increased methyl marks at constitutive heterochromatin on genomic stability remains unclear. Here we show that tethering of both H3K9 and H4K20 methyltransferases to the centromere corrupts genomic stability through loss of centromeric Aurora B. This loss of genomic stability is backed up by analyses of cancer cell line and patient data that show that expression of these genes correlates with aneuploidy, poor patient survival, and sensitivity to Aurora B inhibition. We also show that depletion of H3K9 demethylases also leads to loss of genomic stability. However, this is not through loss of centromeric Aurora B, but perhaps through the DNA damage response. Collectively, these results shed new light on cancer-relevant epigenetic changes in constitutive heterochromatin regulation may underlie genomic instability seen in many different cancer contexts.

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  • etd-5346
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  • 2021
Date created
  • 2021-01-15
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  • 2023-09-27

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