Heterochromatin and its relationship to cell senescence and cancer therapy.

Our goal is to understand the impact of chromatin structure on cell proliferation, cell and tissue aging, cancer and cancer therapies. Senescence associated heterochromatin foci (SAHF) are specialized domains of facultative heterochromatin that form in senescent human cells. Although SAHF are highly compacted domains of heterochromatin, they largely exclude other domains of chromatin at telomeres and pericentromeres, which are themselves thought to be constitutively heterochromatic. The relationship between SAHF formation and these other domains of heterochromatin is discussed. Also, we have obtained evidence for a novel function for a family of heterochromatin proteins, HP1 proteins. We propose that HP1 proteins are essential components of a dynamic nuclear response that senses and rectifies defects in epigenetic information, encoded in chromatin through histone modifications and DNA methylation. Defects in this "chromatin repair" response in transformed cells may contribute to preferential killing of cancer cells by epigenetic cancer therapies, currently in clinical development.