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Peter McHugh

Adrian Harris


Project details:

Recently, we described the accumulation of small cytoplasmic DNA fragments after therapeutic DNA damage, including radiotherapy and chemotherapy (Erdal et al, Genes & Dev. 2017). This induced the expression of a set of interferon (IFN)-stimulated genes comprising the ‘IFN-related DNA damage resistance signature’ (IRDS). The IRDS strongly correlates with resistance to cancer therapy and a worse outcome for patients. While classically, during viral infection, the presence of foreign (viral) DNA in the cytoplasm of host cells initiates type-I IFN production as part of the innate immune system, how ‘self’ DNA is released from the nucleus of cancer cells during therapy to induce IFN signalling remains unknown. Employing deep sequencing and cutting-edge bioinformatic approaches, we aim to reveal the identity of these DNA fragments. Using ultra-resolution microscopy, genome editing techniques and biochemistry, we will define how the DNA fragments are produced. Moreover, we will determine how this ‘self’ DNA engages with the innate immune sensors including the key sensor, cGAS-STING, and analyse induction of the IFN response in clinical breast cancer samples. This will reveal new targets for future therapeutic intervention, and integrate with small molecule inhibitor discovery programmes to target DNA processing enzymes that are underway in our laboratories.