DNA Damage and Innate Immune Responses in Development and Disease

To lessen the “wear and tear” of existence, cells have evolved mechanisms that continuously sense DNA lesions, repair DNA damage and restore their compromised genome back to its native form. Besides genome maintenance pathways, multicellular organisms may also employ adaptive and innate immune mechanisms to guard themselves against foreign threats. Recent evidence points to reciprocal interactions between DNA repair, DNA damage responses and aspects of immunity; both self-maintenance and defense responses share a battery of common players and signaling pathways aimed at safeguarding our bodily functions over time. In the short-term, this functional interplay would allow injured cells to restore damaged DNA templates or communicate their compromised state to the microenvironment. In the long-term, however, it may result in the (premature) onset of age-related degeneration, including cancer. Using a unique series of progeroid animal models with engineered defects in nucleotide excision repair, we will present recent findings on how persistent DNA damage triggers systemic metabolic changes that, in turn, activate innate immunes responses leading to inflammation in the context of tissue-specific pathology and disease progression.