Abstract
<title>Abstract</title> <p> Adult stem cells maintain tissue homeostasis and regenerative capacity throughout life, but the mechanisms that preserve their integrity during aging and stress remain incompletely understood. Hair follicle pigmentation provides a tractable model to study stem cell maintenance as it relies on melanocyte stem cells (McSCs) whose depletion leads to age-related hair greying. Here, we identify the transcription factor BRN2 ( <italic>POU3F2</italic> ) as a key regulator of McSC homeostasis. We show that BRN2 activity is enriched in McSCs and declines with age in both mouse and human hair follicles. Using a melanocyte-specific conditional knockout mouse model, we reveal that loss of Brn2 promotes melanocyte differentiation and accumulation in the hair follicle bulb, accompanied by increased expression of melanocytic genes and a marked downregulation of DNA repair pathways, particularly those involved in nucleotide excision repair and chromosome maintenance. Brn2-deficient cells displayed impaired activation of the DNA damage response following ionizing radiation and entered a p53–p21–associated senescence-like differentiation state rather than undergoing apoptosis. In vivo, Brn2-deficient mice exposed to irradiation-induced stress developed rapid and permanent hair depigmentation associated with depletion of melanocyte lineage cells. Together, these findings identify BRN2 as a suppresor of stress-induced hair greying that links genome maintenance to melanocyte stem cell fate. </p>