SASH1 interacts with TNKS2 and promotes human melanocyte stem cell maintenance

ABSTRACTBoth aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1S519Nvariant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1S519Nwas defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1’s promotion of stem-like function. Further, the SASH1S519Nvariant is in abona fideTankyrase-binding motif, and SASH1S519Nalters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.