Noncanonical translation via deadenylated 3' UTRs maintains primordial germ cells PMID: 29988067

ADC Targets in Oncology

2026-04-10

Noncanonical translation via deadenylated 3' UTRs maintains primordial germ cells

Nat Chem Biol. 2018 Sep;14(9):844-852. doi: 10.1038/s41589-018-0098-0.

Youngnam N Jin ¹ ² ³ ⁴ ⁵ ⁶ , Peter J Schlueter ⁷ ⁸ ⁹ , Nathalie Jurisch-Yaksi ⁷ ⁸ ⁹ , Pui-Ying Lam ⁷ ⁸ ⁹ ¹⁰ ¹¹ ¹² , Shan Jin ⁷ ⁸ ⁹ , Woong Y Hwang ⁷ ⁸ , Jing-Ruey Joanna Yeh ⁷ ⁸ ⁹ , Masaaki Yoshigi ¹³ , Shao-En Ong ¹¹ ¹⁴ , Monica Schenone ¹¹ , Christina R Hartigan ¹¹ , Steven A Carr ¹¹ , Randall T Peterson ¹⁵ ¹⁶ ¹⁷ ¹⁸ ¹⁹ ²⁰

Affiliations

1. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA. [email protected].
2. Department of Medicine, Massachusetts General Hospital, Charlestown, MA, USA. [email protected].
3. Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
4. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected].
5. Broad Institute, Cambridge, MA, USA. [email protected].
6. College of Pharmacy, University of Utah, Salt Lake City, UT, USA. [email protected].
7. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
8. Department of Medicine, Massachusetts General Hospital, Charlestown, MA, USA.
9. Department of Medicine, Harvard Medical School, Boston, MA, USA.
10. Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
11. Broad Institute, Cambridge, MA, USA.
12. College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
13. Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
14. Department of Pharmacology, University of Washington, Seattle, WA, USA.
15. Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA. [email protected].
16. Department of Medicine, Massachusetts General Hospital, Charlestown, MA, USA. [email protected].
17. Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
18. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected].
19. Broad Institute, Cambridge, MA, USA. [email protected].
20. College of Pharmacy, University of Utah, Salt Lake City, UT, USA. [email protected].

Abstract

Primordial germ cells (PGCs) form during early embryogenesis with a supply of maternal mRNAs that contain shorter poly(A) tails. How translation of maternal mRNAs is regulated during PGC development remains elusive. Here we describe a small-molecule screen with zebrafish embryos that identified primordazine, a compound that selectively ablates PGCs. Primordazine's effect on PGCs arises from translation repression through primordazine-response elements in the 3' UTRs. Systematic dissection of primordazine's mechanism of action revealed that translation of mRNAs during early embryogenesis occurs by two distinct pathways, depending on the length of their poly(A) tails. In addition to poly(A)-tail-dependent translation (PAT), early embryos perform poly(A)-tail-independent noncanonical translation (PAINT) via deadenylated 3' UTRs. Primordazine inhibits PAINT without inhibiting PAT, an effect that was also observed in quiescent, but not proliferating, mammalian cells. These studies reveal that PAINT is an alternative form of translation in the early embryo and is indispensable for PGC maintenance.