Chandler, H; (2013) Association of CK2 with Polycomb complexes and its functional implications. Doctoral thesis , UCL (University College London).

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Abstract

Polycomb group (PcG) proteins are important for establishing the patterns of gene expression in different cell types and are critical for the maintenance of pluripotency. They participate in multi-component complexes, such as Polycomb repressive complex 1 (PRC1), which modify, and bind to, histone tails. A number of auxiliary proteins consistently associate with PRC1, including the three subunits of protein kinase CK2 (CK2). The work described in this thesis investigates the interaction of CK2 with PRC1 components and the implications for PRC1 function. The data suggest that CK2 can directly bind to members of the CBX family, the mammalian orthologues of Polycomb in Drosophila. In the case of CBX7, residues within the conserved Pc box, near the C-terminus, were critical for this interaction. Interestingly, these residues were also required for the interaction between CBX7 and RING2, another core component of mammalian PRC1. Whether CBX7 is phosphorylated by CK2 remains equivocal and likewise, it has been difficult to demonstrate a role for CK2 in the ability of CBX7 to function as a transcriptional repressor. In addition to their role as regulators of gene expression, PcG proteins have been recently implicated in the DNA damage response (DDR). Moreover, several proteins involved in the DDR are known to be CK2 substrates. To explore the link between CK2 and PRC1 in the context of DNA damage, a cell system was established in which multiple sequence-specific double-strand breaks (DSBs) could be induced in human diploid fibroblasts. Interestingly, detection of PRC1 proteins by both immunofluorescence and genome-wide ChIP-seq suggests that they are not recruited to DSBs in this system. Furthermore, the data indicate that extensive DNA damage does not mobilise PRC1 complexes from known binding sites.

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