PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation
Jeanette A. Johansson, Kerrie L. Marie, Yuting Lu, Alessandro Brombin, Cristina Santoriello, Zhiqiang Zeng, Judith Zich, Philippe Gautier, Alex von Kriegsheim, Hannah Brunsdon, Ann P. Wheeler, Marcel Dreger, Douglas R. Houston, Christopher M. Dooley, Andrew H. Sims, Elisabeth M. Busch‐Nentwich, Leonard I. Zon, Robert S. Illingworth, E. Elizabeth Patton
Abstract
Melanocytes, replenished throughout life by melanocyte stem cells (MSCs), play a critical role in pigmentation and melanoma. Here, we reveal a function for the metastasis-associated phosphatase of regenerating liver 3 (PRL3) in MSC regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at master transcription factor (MITF)-regulated endolysosomal vesicle genes. In zebrafish, this mechanism controls premature melanoblast expansion and differentiation from MSCs. In melanoma patients, restricted transcription of this endolysosomal vesicle pathway is a hallmark of PRL3-high melanomas. Our work presents the conceptual advance that PRL3-mediated control of transcriptional elongation is a differentiation checkpoint mechanism for activated MSCs and has clinical relevance for the activity of PRL3 in regenerating tissue and cancer.