Autophagy repurposes cells during paligenosis.

Differentiated cells have evolved paligenosis, a conserved program to return to a stem or progenitor state and reenter the cell cycle to fuel tissue repair. Paligenosis comprises three sequential stages: 1) quenching of MTORC1 activity with induction of massive macroautophagy/autophagy that remodels differentiated cell architecture; 2) induced expression of progenitor/repair-associated genes; 3) MTORC1 reactivation with cell cycle reentry. Here, we summarize work showing that evolutionarily conserved genes - Ddit4 and Ifrd1 - are critical regulators of paligenosis. DDIT4 suppresses MTORC1 function to induce lysosomes and autophagosomes in paligenosis stage 1. As DDIT4 decreases during paligenosis, TRP53 continues MTORC1 suppression until cells are licensed to reenter the cell cycle by IFRD1 suppression of TRP53. Cells with DNA damage maintain TRP53 until either the damage is repaired, or they undergo apoptosis. The concept of paligenosis and identification of paligenosis-dedicated genes may provide new angles to harness tissue regeneration and specifically target tumor cells.