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Frescas D , Guardavaccaro D , Kuchay SM , Kato H , Poleshko A , Basrur V , Elenitoba-Johnson KS , Katz RA , Pagano M
KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state
Cell Cycle. 2008 Nov;7(22) :3539-3547
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Heterochromatin plays an essential role in the preservation of epigenetic information, the transcriptional repression of repetitive DNA elements and inactive genes, and the proper segregation of chromosomes during mitosis. Here we identify KDM2A, a JmjC-domain containing histone demethylase, as a heterochromatin-associated and HP1-interacting protein that promotes HP1 localization to chromatin. We show that KDM2A is required to maintain the heterochromatic state, as determined using a candidate-based approach coupled to an in vivo epigenetic reporter system. Remarkably, a parallel and independent siRNA screen also detected a role for KDM2A in epigenetic silencing. Moreover, we demonstrate that KDM2A associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Dissecting the relationship between heterochromatin and centromeric RNA transcription is the basis of ongoing studies. We demonstrate that forced expression of these satellite RNA transcripts compromise the heterochromatic state and HP1 localization to chromatin. Finally, we show that KDM2A is required to sustain centromeric integrity and genomic stability, particularly during mitosis. Since the disruption of epigenetic control mechanisms contributes to cellular transformation, these results, together with the low levels of KDM2A found in prostate carcinomas, suggest a role for KDM2A in cancer development.
Frescas, David Guardavaccaro, Daniele Kuchay, Shafi M. Kato, Hiroyuki Poleshko, Andrey Basrur, Venkatesha Elenitoba-Johnson, Kojo S. Katz, Richard A. Pagano, Michele LANDES BIOSCIENCE 372IA