Abstract
The RNA binding protein DEAD-END (DND1) is one of the few proteins known to regulate microRNA (miRNA) activity at the level of miRNA-mRNA interaction. DND1 blocks miRNA interaction with the 3′-untranslated region (3′-UTR) of specific mRNAs and restores protein expression. Previously, we showed that the DNA cytosine deaminase, APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide like 3), interacts with DND1. APOBEC3 has been primarily studied for its role in restricting and inactivating retroviruses and retroelements. In this report, we examine the significance of DND1-APOBEC3 interaction. We found that while human DND1 inhibits miRNA-mediated inhibition of P27, human APOBEC3G is able to counteract this repression and restore miRNA activity. APOBEC3G, by itself, does not affect the 3′-UTR of P27. We found that APOBEC3G also blocks DND1 function to restore miR-372 and miR-206 inhibition through the 3′-UTRs of LATS2 and CX43, respectively. In corollary experiments, we tested whether DND1 affects the viral restriction function or mutator activity of APOBEC3. We found that DND1 does not affect APOBEC3 inhibition of infectivity of exogenous retrovirus HIV (ΔVif) or retrotransposition of MusD. In addition, examination of Ter/Ter;Apobec3−/− mice, lead us to conclude that DND1 does not regulate the mutator activity of APOBEC3 in germ cells. In summary, our results show that APOBEC3 is able to modulate DND1 function to regulate miRNA mediated translational regulation in cells but DND1 does not affect known APOBEC3 function.
Highlights
The RNA binding protein DEAD-END (DND1) is essential for germ cell viability [1,2]
Because 3′UTR of human P27 has been characterized to contain two DND1 binding sites flanked by miR-221 binding sites (Figure 1a) [4], constructs encoding human P27 were predominantly used in these assays, together with human DND1 and APOBEC3G
This function of APOBEC3G appears to apply to multiple Messenger RNA (mRNA) targets of DND1 as APOBEC3G has a similar effect on P27, Serine/threonine-protein kinase (LATS2) and CX43
Summary
The RNA binding protein DEAD-END (DND1) is essential for germ cell viability [1,2]. When Dnd is functionally inactivated, as in the Ter mutant mouse strain, this results in death of germ cells, sterility [2], and in some cases development of testicular germ cell tumors [2,3].DND1 encodes canonical RNA recognition motifs [1,4] through which it interacts with the 3′-UTRs of mRNAs. The RNA binding protein DEAD-END (DND1) is essential for germ cell viability [1,2]. When Dnd is functionally inactivated, as in the Ter mutant mouse strain, this results in death of germ cells, sterility [2], and in some cases development of testicular germ cell tumors [2,3]. DND1 encodes canonical RNA recognition motifs [1,4] through which it interacts with the 3′-UTRs of mRNAs. For example, DND1 inhibits miR-221 function from the 3′-UTR of P27 resulting in increased P27 protein expression [4,5]. DND1 has been shown to inhibit miR-372 from the 3′-UTRs of LATS2 (serine/threonineprotein kinase, large tumor suppressor, homolog 2) and miRNA association with mRNA usually results in translation inhibition or degradation of mRNA. DND1 may bind and sequester mRNAs away from miRNA access
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