Regulation of SUMO in DNA double-strand break repair.

Proper repair of DNA double-strand breaks (DSBs) is vital to immunological health, cancer protection and healthy ageing. The cellular response to this form of damage is highly co-ordinated by a series of diverse post-translational modifications. Recently we, and others, demonstrated a vital role for the small-ubiquitin like modifiers (SUMOs) in the DSB response. Despite an emerging picture of the mammalian SUMO-proteome our understanding of the regulation of SUMOylation following DNA damage is superficial and our current knowledge points to a largely passive process. Contrary to the current prevailing view of SUMOylation we hypothesise that the regulation of this modification in the DSB response is highly coordinated. We suggest this regulation is fundamental to correct DNA repair. Our aims are to identify mechanisms of SUMO enzyme cascade initiation, to establish how SUMO proteases perform the vital role of maintaining the balance of SUMO conjugates during DNA damage signalling, and to describe the features of a novel subclass of SUMO target modification site critical to the cellular response to DSBs. In achieving these aims we anticipate this programme will underpin future developments relevant to cancer treatment and healthy ageing by identifying new areas of regulation and cross-talk in the DNA repair process.