Phosphorylation and DNA damage resolution coordinate SOX2-mediated reprogramming in vivo.

The stem cell factor SOX2 can reprogram resident glial cells into neurons in the adult mammalian central nervous system, but the molecular mechanisms underlying this process remain poorly understood. Here, we show that both SOX2 phosphorylation and the PRKDC-dependent nonhomologous end joining (NHEJ) pathway are essential for SOX2-mediated in vivo glia-to-neuron reprogramming. A phospho-mimetic SOX2 mutant significantly enhances reprogramming output without altering neuronal fate. Conversely, loss of PRKDC or knockdown of core NHEJ components KU80 and LIG4 abolishes reprogramming. Notably, p53 knockdown restores reprogramming in PRKDC-deficient mice, likely by overcoming DNA damage-induced cell-cycle arrest. These findings demonstrate that SOX2-driven glial reprogramming requires both precise posttranslational regulation and effective DNA damage repair and suggest that targeting these pathways could enhance regenerative strategies in the CNS.