Signalling Pathways Mediating Tissue Functionality Following DNA Damage in Caenorhabditis elegans

Aging can be defined as a progressive loss of physiological integrity leading to functional decline. Accumulation of DNA damage is a well-known driving factor of the aging process and different premature aging diseases are associated with accumulation of unrepaired DNA lesions, due to deficiencies in genome maintenance pathways such as the Nucleotide Excision Repair (NER) pathway. Cell-autonomous DNA damage responses and their outcomes have been well characterized in the past; however, little is known about the systemic responses to genome instability and how tissue functionality is maintained when DNA damage accumulates. There have been previous indications of systemic stress responses in Caenorhabditis elegans, many of which appear to be coordinated by the neuronal system. Recently, a proteome analysis of NER-deficient animals revealed many proteins involved in regulation of the neuronal synaptic machinery and modulation of certain neuronal pathways to be upregulated following UV exposure, suggesting a role of neuronal signaling and, possibly, specific signaling pathways, in promoting an adaptive “survival response” aiming to maintain tissue functionality after persistent DNA damage.

To evaluate the contribution of different tissues in mediating an overall resistance to UV in C. elegans, we developed different tissue-specific XPA-1 rescue lines in an xpa-1-deficient background. We show here that neuron-specific functional DNA repair is able to significantly rescue the decline of tissue function following DNA damage in a NER-deficient background. To identify signaling pathways coordinating this response, we are currently following a candidate gene approach, focused on genes involved in neuropeptide and neurotransmitter signaling.