Rtl3 (retrotransposon Gag-like protein 3; also Zcchc5, Mar3/Mart3) is the mouse ortholog of human RTL3, an X-linked eutherian gene domesticated from the gag region of a Ty3/gypsy sushi-ichi-related LTR retrotransposon. The 553-residue protein has a large disordered N-terminal region, a retroviral capsid (CA)-like domain and a C-terminal CCHC-type zinc knuckle (C-x2-C-x4-H-x4-C) of the nucleocapsid type. In mouse and many other mammals the ancestral aspartyl-protease region is retained in the -1 reading frame overlapping the gag ORF, so Rtl3 likely encodes a CA-PR fusion via a programmed ribosomal frameshift; the reviewed UniProt entry corresponds to the gag (CA-NC) product. Rtl3 is a nuclear protein with a CCHC DNA-binding motif and functions as a transcriptional/gene-regulatory factor. It is expressed in embryonic myogenic progenitor cells, and its overexpression restrains muscle satellite-cell self-renewal; the human ortholog regulates the chondrogenic SOX9->COL2A1 program. Direct nucleic-acid targets of the mouse protein have not been defined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular function ND annotation: when it was made, no molecular function had been curated for this gene product from literature. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the molecular function is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. PMID:27446912 mentions the CCHC motif only as background in its introduction. The gene's own literature-search record (OpenScientist deep research) finds no study showing Rtl3 itself binds a nucleic acid or has another activity. Supporting Evidence: file:mouse/Rtl3/Rtl3-deep-research-openscientist.md Rtl3 itself has not been shown to form particles or bind a defined nucleic acid in vitro. |
| GO:0003676 nucleic acid binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the retroviral-type CCHC zinc knuckle (residues 523-537). Reason: The CCHC knuckle is the canonical nucleic-acid-binding module of Gag nucleocapsids and is conserved and intact in mouse Rtl3; the ortholog is described as a nuclear CCHC DNA-binding protein. Direct DNA-vs-RNA binding has not been measured, so the general term is as specific as the evidence allows. Accepted. Supporting Evidence: PMID:27446912 Zcchc5 encodes a nuclear protein containing a CX2CX4HX4C DNA-binding motif, also called CCHC domain, allowing DNA binding to regulate transcription. |
| GO:0005575 cellular_component | ND GO_REF:0000015 | ACCEPT | Summary: Root cellular component ND annotation: when it was made, no cellular component had been curated for this gene product from literature. Reason: ACCEPT under the ND acceptance rule (projects/NO_DATA.md). The evidence this review cites for the cellular component is inferred (from orthologs, family membership or sequence features) or comes from other species; none of it is literature on this gene product in this species. This was judged from the review's own content during the NO_DATA re-action pass, not from a new literature search. Earlier action: MODIFY. PMID:27446912 calls Zcchc5 nuclear only as background in its introduction; the nucleus row is IEA. The gene's own literature-search record (OpenScientist deep research) finds the localization unresolved, with no mouse localization study. Supporting Evidence: file:mouse/Rtl3/Rtl3-deep-research-openscientist.md **Unresolved subcellular localization.** Nuclear (curated) vs. cytoplasmic-granular (antibody atlas) — not reconciled. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping; Zcchc5 is reported as a nuclear protein. Reason: Consistent with the experimental description of Zcchc5 as a nuclear protein with a CCHC DNA-binding motif and with its proposed transcriptional-regulator role. Accepted. Supporting Evidence: PMID:27446912 Zcchc5 encodes a nuclear protein containing a CX2CX4HX4C DNA-binding motif, also called CCHC domain, allowing DNA binding to regulate transcription. |
| GO:0008150 biological_process | ND GO_REF:0000015 | MODIFY | Summary: Root-level placeholder indicating no biological process had been assigned when the ND annotation was made. Reason: Out of date. Overexpression of Zcchc5 decreases muscle satellite-cell self-renewal capacity, and the gene is repressed as satellite cells emerge, implicating it in regulation of satellite-cell self-renewal / postnatal myogenesis. The ND placeholder should be replaced by that process term. Zcchc5 itself supplies the regulatory (nuclear CCHC) input, satisfying participation. Proposed replacements: regulation of skeletal muscle satellite cell proliferation Supporting Evidence: PMID:27446912 ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from the CCHC zinc knuckle; the three Cys and one His coordinate a structural zinc ion. Reason: The CCHC motif (mouse C-LYCGHPGHFARDC) is a bona fide zinc-coordinating module, conserved from human RTL3. Accepted as a supporting molecular-function term. Supporting Evidence: PMID:16093683 In addition, three Mar proteins have conserved the Gag CCHC zinc finger motif, suggesting a role in nucleic acid binding. |
Loading supporting content…
Download this section (compressed HTML)Q: Does mouse Rtl3 express a CA-PR fusion protein via programmed -1 frameshifting, and if so does the protease region have any activity or is it a structural relic?
Q: What nucleic-acid or transcriptional targets does Rtl3/Zcchc5 engage to limit muscle satellite-cell self-renewal?
Experiment: Generate Rtl3 loss- and gain-of-function in myogenic progenitors / satellite cells and measure self-renewal, differentiation, and transcriptome; map DNA/RNA targets by ChIP-seq/CLIP-seq on tagged Rtl3.
Hypothesis: Rtl3/Zcchc5 acts as a nuclear gene-regulatory factor that limits satellite-cell self-renewal.
Experiment: Use ribosome profiling and mass spectrometry to test for the frameshift product and characterise its localisation and any residual protease activity.
Hypothesis: The -1 frameshift CA-PR fusion predicted for mouse Rtl3 is expressed.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)