Identification of novel protein interactions within DNA damage pathways regulated by non-canonical and novel DNA damage kinases. (360G-Wellcome-200462_Z_16_Z)

DNA damage response (DDR) pathways protect cells from genome instability and cancer development. They are regulated by canonical and non-canonical DDR kinases; the latter are mainly involved in signalling pathways other than DDR. Little is known about the role of the non-canonical kinases in regulation of DDR and in the interplay between DDR and other cellular processes. In addition, a large number of DDR proteins contain phosphorylated consensus sites of kinases previously notidentified as DDR regulators. Although the role of these sites in DDR is not clear, many are mutated in cancer and/or their phosphorylation status changes upon DNA damage, highlighting their functional importance. Here I propose A) Identification of new protein-protein interactions dependent on the phosphorylation of specific sites targeted by non-canonical and novel DDR kinases by proteomic approach B) Characterisation of their functional relevance in DDR using combination of molecular cell- biology and biochemical experiments C) Determination of kinases regulating the phospho-dependent interactions. This project aims to fill in the gap and uncover a new spectrum of molecular mechanisms involved in DDR, identify their regulators and provide insight into the relationships between DDR and other signalling pathways.