Taking damage as an advantage: Adaptation of Drosophila hemocyte functions upon DNA damage

Immune cells in invertebrates and vertebrates are constantly exposed to environmental stressors, such as oxidative stress, UV radiation, toxins or infection, causing cellular damage of lipids, proteins but also DNA. Unresolved DNA damage in immune cells compromises genome integrity and stability, and can result in cellular dysfunction, apoptosis, or senescence and thereby contributing to immunodeficiencies, cancer or chronic inflammatory diseases. To counteract the effects and maintain genome integrity, cells employ a highly conserved DNA damage response (DDR) machinery. Beyond its canonical role of DNA repair, DDR has emerged as an active regulator of diverse physiological functions. This non-canonical (nc)DDR has been connected in the regulation of immune cells in vertebrates and invertebrates. Especially in Drosophila melanogaster it has been shown that ncDDR guides both lineage differentiation and functional adaptation during immune responses. These findings link ncDDR and genome plasticity to regulation of cell fate decisions and functional specialization of hemocytes and make Drosophila an attractive tool to dissect the role of ncDDR in immune cells during development, health but also disease settings. In this review, we discuss and summarize the available literature on the emerging concept of ncDDR as a critical layer of immune cell development and function in Drosophila and potentially similar mechanisms in mammals.