PRL3-DDX21 transcriptional control of endolysosomal genes restricts melanocyte stem cell differentiation

Jeanette Johansson, Kerrie L. Marie, Yuting Lu, Alessandro Brombin, Cristina Santoriello, Zhiqiang Zeng, Judith Zich, Phillipe 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 Illingworth, E Elizabeth Patton

Research output: Contribution to journalArticlepeer-review

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 melanocyte stem cell regeneration. We show that PRL3 binds to the RNA helicase DDX21, thereby restricting productive transcription by RNAPII at 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.
Original languageEnglish
Pages (from-to)317-332.E9
Number of pages16
JournalDevelopmental Cell
Volume54
Issue number3
Early online date10 Jul 2020
DOIs
Publication statusPublished - 10 Aug 2020

Keywords

  • zebrafish
  • melanocyte stem cell
  • small molecule screen
  • regeneration
  • PRL3
  • PTP4A3
  • transcription elongation
  • MITF
  • DDX21
  • melanoma

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