Abstract
The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.
Highlights
Division of Experimental Oncology, Department of Oncology, Faculty of Medicine & Dentistry, Abstract: The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications
In AML cells, 50% of the genes downregulated by protein arginine methyltransferase 5 (PRMT5) inhibition were partially rescued in expression upon inhibition of EZH2 activity, providing evidence of the critical role for PcG repressive complex 2 (PRC2)-EZH2 in meth
While retaining PRC1 assembly results in a complete loss of H2AK119 monoubiquitylation in vivo, subsequent displacement of PRC2 activity, loss of H3K27me3 deposition, loss of canonical PRC1 recruitment and loss of target gene repression in embryonic stem cells (ESCs) [80]. These findings indicate PRC1 catalytic activity is essential for Polycomb-mediated gene repression and chromatin domain interactions
Summary
The EZH2 paralog EZH1 was associated with the transcriptionally active epigenetic mark H3K4me, RNA polymerase II (RNAPII), and mRNA production [51] These studies suggest PcG proteins may have additional roles different from their repressive functions in development. 1991 [71], and encode proteins that are the core components of the mammalian PRC1 system, RING1A ( known as RING1) and RING1B ( known as RING2) [72] These two proteins, in complex with a PSC member (such as BMI1), form the E3 ubiquitin ligase that catalyzes the PcG-dependent ubiquitylation of histone H2A. The E2F6.com-1 complex, which binds to and represses MYC and E2F6-responsive genes during the G0 stage of the cell cycle, contains several PcG proteins including RING1A, RING1B, MBLR (PCGF6), h-L3MBTL and YAF2. These complexes raise the possibility that the RING1 proteins could have other functions not associated with PRC1
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