Journal
DEVELOPMENTAL CELL
Volume 54, Issue 3, Pages 317-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2020.06.013
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Funding
- CRUK [C588/A19167, C8216/A6129, C588/A10721]
- NIH [CA83115]
- MRC Career Development award [MR/S007644/1]
- Simons Initiative for the Developing Brain [SFARI 529085]
- MRC HGU studentship
- NIH Intramural Research Program
- Wellcome Trust [098051, 206194, 208402/Z/17/Z]
- ERC [694289]
- Cancer Biology [R01 CA103846]
- NIH Melanoma PPG [P01CA63222]
- Melanoma Research Alliance
- Starr Cancer Consortium grant
- MRC HGU Programme [MC_UU_00007/9]
- European Research Council [ZF-MEL-CHEMBIO-648489]
- L'Oreal-Melanoma Research Alliance [401181]
- MRC [MR/K017047/1, MC_UU_00007/9, MR/S007644/1] Funding Source: UKRI
- European Research Council (ERC) [694289] Funding Source: European Research Council (ERC)
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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.
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