PMID:28297718

Citation	Yamaji, M, Jishage, M, Meyer, C, Suryawanshi, H, Der, E, Yamaji, M, Garzia, A, Morozov, P, Manickavel, S, McFarland, HL, Roeder, RG, Hafner, M and Tuschl, T' (2017) DND1 maintains germline stem cells via recruitment of the CCR4-NOT complex to target mRNAs. Nature '
Abstract	The vertebrate-conserved RNA-binding protein DND1 is required for the survival of primordial germ cells (PGCs), as well as the suppression of germ cell tumours in mice. Here we show that in mice DND1 binds a UU(A/U) trinucleotide motif predominantly in the 3' untranslated regions of mRNA, and destabilizes target mRNAs through direct recruitment of the CCR4-NOT deadenylase complex. Transcriptomic analysis reveals that the extent of suppression is dependent on the number of DND1-binding sites. This DND1-dependent mRNA destabilization is required for the survival of mouse PGCs and spermatogonial stem cells by suppressing apoptosis. The spectrum of target RNAs includes positive regulators of apoptosis and inflammation, and modulators of signalling pathways that regulate stem-cell pluripotency, including the TGFβ superfamily, all of which are aberrantly elevated in DND1-deficient PGCs. We propose that the induction of the post-transcriptional suppressor DND1 synergizes with concurrent transcriptional changes to ensure precise developmental transitions during cellular differentiation and maintenance of the germ line.
Links	PubMed Online version:10.1038/nature21690
Keywords
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:DND1		GO:0043066: negative regulation of apoptotic process	ECO:0000314:		P		Paper's Protein Name: RNA-binding protein DND1. UniProt's Protein Name: Dead end protein homolog 1. Organism: Mus musculus (Mouse). Notes: This paper deals with the destabilization of specific mRNA segments by the protein Dnd1. One example of this involves apoptosis. When Dnd1 is mutated and loses function, there is “an upregulation of DND1 PAR-CLIP targets... including positive regulators of apoptosis.” More importantly, Extended figure 6g shows that after GSCs are transduced with DND1’s shRNA targets, cell death occurs within 4 days. The paper also states that “Annexin V-positive cells represent early apoptotic cells and are gated as P8 population (green)” in Extended Figure 6i. As can be seen in the figure, there are clearly more “early apoptotic cells” when the cells in question are transduced with DND1’s shRNA targets. It appears that the process for transduction was done with shRNA targets originating from mice, as is listed in Supplementary Table 9.	complete CACAO 12319
MOUSE:DND1		GO:0023056: positive regulation of signaling	ECO:0000314:		P		Paper's Protein Name: RNA-binding protein DND1. UniProt's Protein Name: Dead end protein homolog 1. Organism: Mus musculus (Mouse). Notes: “Pathway analysis of the top 300 DND1 targets showed enrichment for genes associated with signalling pathways regulating pluripotent stem cells and cancer development (for example, TGFβ, WNT and PI3K–AKT signalling) (Extended Data Fig. 4, Supplementary Table 3)."	complete CACAO 12320
HUMAN:DND1		GO:0061158: 3'-UTR-mediated mRNA destabilization	ECO:0000314:		P		Organism: Homo sapiens. UniProt’s Name: Dead end protein homolog 1. Paper’s Name: RNA-binding protein DND1. Notes: Extended Figure 2g is primarily used, though other figures help to understand the findings. For instance, the paper had previously indicated that DND1 is responsible for mRNA destabilization, and showed in Figure 1E that with an increase in number of DND1 binding sites lead to a greater decrease in median transcript abundance. More importantly, the paper states that “only binding sites located in the 3′ UTR contributed to the DND1-mediated target mRNA reduction.” Extended Figure 2g indeed shows that mRNA targets (of DND1) with binding sites in the 3’-UTR region also have a greater decrease in median transcript abundance. As this data primarily makes use of “FH–DND1-expressing HEK293 cells,” this is a human protein, not a mouse protein.	complete CACAO 12373

References

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