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Screen to identify heterochromatin promoting drugs


Heterochromatin is a tightly packed form of DNA associated with gene silencing and plays a significant role in the regulation of gene expression, segregation of chromosomes during mitosis and protection of genome stability and integrity. Heterochromatin is also becoming more recognized to be implicated in cancer and may serve as a potential target for cancer therapy. To our knowledge, there are no drugs that are well-established to promote heterochromatin. Here, we describe and perform two simple screening methods to identify compounds that may promote heterochromatin. We screened Oncology Set III, a set of FDA approved oncology drugs, using DX1 mutant flies whose eye color phenotype is sensitive to heterochromatin levels. This screen produced no hits and was inconclusive. We then screened Natural Set II, a set of natural compounds, using a cell based method. One drug, streptonigrin, increased the brightness and induced the formation of visible foci of DNA stain Hoechst 33258 in HeLa cell nuclei, indicative of increase in heterochromatin levels. We then showed that Heterochromatin Protein 1 alpha (HP1[alpha]) foci co- localizes with DNA foci in streptonigrin treated cells, further indicating the drug affects heterochromatin formation. The induction of heterochromatin reorganization by streptonigrin was also seen to be concentration dependent in 3T3 cells by observation of nuclear morphology. These results show that streptonigrin may promote heterochromatin formation. Interested in looking at the capabilities of streptonigrin to prevent cancer growth without significantly affecting cell proliferation or viability, we also established non-lethal concentrations of streptonigrin in vivo

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