Investigating the role of CK2 in the DNA damage response

Miller, Edward Strenk (2014). Investigating the role of CK2 in the DNA damage response. University of Birmingham. Ph.D.

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Abstract

Casein Kinase 2 (CK2) is a ubiquitous serine/threonine kinase. Due to its pleiotropic nature CK2 is involved in a multitude of cellular pathways including cell survival, proliferation and apoptosis. Therefore it has come as no surprise that a requirement for CK2 activity has been
identified during the repair of DNA damage. Here we have described a novel role for CK2 in the response to DNA double-strand breaks. We have shown the mediator of DNA damage checkpoint 1 (MDC1) is constitutively phosphorylated by CK2, which is required for an interaction with the MRE11/RAD50/NBS1 (MRN) complex, via the FHA domain of NBS1.
Moreover, disruption of this interaction resulted in loss of MRN foci following ionizing radiation and a partial G2/M checkpoint defect. Furthermore, the identification of three
siblings presenting NBS/Seckel-like phenotypes with a unique mutation in the BRCT domain of NBS1, that phenocopied some of our observations, provided additional evidence for the importance of phospho-dependent interactions within the cell. Lastly, the identification of putative CK2 target residues in MRE11 and our preliminary data suggest that the kinase may play further roles in regulating the activity of the MRN complex that lie outside its activity in DNA double-strand break repair.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):