The role of phospho/methyl switch mechanisms in regulation of nuclear processes

Abstract

The DNA of eukaryotes is packed into chromatin, a nucleoprotein complex that is subject to continuous adjustments, in order to regulate nuclear processes, such as transcription, mitosis and DNA-damage repair. Chromatin is build up out of nucleosomes, structures in which DNA is wrapped around a protein complex consisting of histones. These histones are subject to a wide range of post-translational modifications (PTMs) that are actively deposited and removed, in response to upstream signals. These PTMs act in a combined or consecutive manner, and can be recognized by specific proteins, 'readers,' that will determine their biological outcome. This intercommunication between histone PTMs is referred to as crosstalk. In regulation of chromatin function, direct changes can be required, for instance after growth factor stimulation or at the onset of mitosis. For this purpose, the cell uses histone 'switch' mechanisms, to instantaneously alter the biological output. This can be established by the addition of a phosphate on a tyrosine or serine, that functions as a switch for readers of adjacent lysine residues. In this thesis, the function of several histone phospho/methyl switch mechanisms are being discussed.