The role of DNA damage response proteins in innate immune signalling: a new role for BRCA1

Thesis

Pattern Recognition Receptors (PRRs), which have evolved to detect a diverse array of pathogenic features known as Pathogen Associated Molecular Patterns (PAMPs), are localised optimally for interaction with their cognate ligands. Upon Receptor activation, signal transduction pathways are induced which converge at different points to direct a specific inflammatory response. TBK1 is activated and recruited to multiple PRRs, where it in turn recruits and phosphorylates IRF3 which then translocates to the nucleus and induces the expression of type I IFN. In this study, the major breast cancer susceptibility protein BRCA1, known for its functional role in maintaining genomic stability, is found to be phosphorylated following PRR triggering. This event is demonstrated to be DNA Damage, DNA Damage Response (DDR) signalling, and oxidative stress-independent. Further to this, phosphorylated BRCA1 localises to Golgi-related microsomes in perinuclear zones where TBK1 and the adaptor STING can be found. Here, BRCA1 interacts biochemically with and facilitates full activation of TBK1. BRCA1-deficient cells show abrogated IRF3 phosphorylation, type I IFN production and ISG induction in response to a diverse array of PRR agonists as well as both HSV1 and Sendaï virus (SeV). Subsequently, BRCA1 deficiency impairs antiviral responses to pathogens such as HSV1.

Authors: Gaughan, D

• DOI: 10.5287/ora-vqrvqq5qx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English