The role and regulation of nuclear myosins in DNA damage

Unconventional myosins have often been characterised within the cytoplasm of the cell, however little work has been done to characterise their role within the nucleus. The first nuclear myosin was identified within the 1990s and since then eight types of myosin have been found within the nucleus. The first to be found and the one myosin that has been heavily characterised is nuclear myosin 1. This myosin has a role in transcription, as well as chromatin movement after DNA damage. Myosin VI another myosin recently found in the nucleus has also been attributed to stable transcription, and, like nuclear myosin 1 can also bind to the RNA polymerase II complex.

So far, a full length structure of nuclear myosin I is yet to be defined, here in this thesis, using typical biochemical techniques, an interaction between the N-terminus of the protein and the nuclear localisation sequence has been identified, along with disassociation constants, that finally show a direct interaction between DNA and the myosin. As well as this, MVI has had another role in the nucleus, which is observed after the induction of double strand breaks within DNA. This thesis discusses why MVI is vital for double strand break signalling, as cellular biology techniques have shown the lack of γH2AX signalling the motor domain of MVI is inhibited. Not only is a working MVI necessary for when signalling DNA damage, this thesis has also found direct interactions with histones and their modifiers.

As both nuclear myosins are involved in transcription, this thesis has looked at how these two myosins interact, and looks further into their nuclear import, roles in the DNA damage response, and how they are regulated within these roles.