Distinct signaling signatures drive compensatory proliferation via S-phase acceleration

Author summary Regeneration requires high levels of cell proliferation to restore the physiological function a damaged tissue. This can either be achieved by allowing more cells to enter the cell cycle, or by accelerating cell cycle progression. In addition, the spatio-temporal dynamics of proliferation need to account for differences in the types and degree of damage. How different tissue damage environments, proliferative signals and cell cycle controls are integrated to drive tissue regeneration is little understood. We address this open question in regenerating Drosophila imaginal discs. We demonstrate that inflammatory and non-inflammatory damage activate distinct proliferative signaling pathways, which accelerate cell cycle progression via reducing gap phase length. Despite the risk of inducing replicative stress and compromising genome integrity, we find that nucleotide incorporation during DNA replication is strongly and safely accelerated, thereby also reducing S-phases length. Our work thus provides an unprecedented perspective on the convergence of different damage and signaling environments on the same regenerative cell cycle program.