MKRN1 (makorin RING finger protein 1; RNF61) is a cytoplasmic RNA-binding RING-type E3 ubiquitin ligase of the makorin family. It combines a C3HC4 RING domain, which confers ubiquitin-protein ligase activity, with multiple CCCH/C3H zinc-finger motifs that mediate RNA binding. MKRN1 ubiquitinates several substrate proteins - including p53/TP53 (which it suppresses under normal conditions to keep cells alive), the CDK inhibitor CDKN1A/p21 (which it degrades under stress to promote apoptosis), the telomerase catalytic subunit TERT (acting as a negative regulator of telomerase), and FILIP1 - thereby influencing cell-cycle arrest, apoptosis and telomere maintenance. In addition, MKRN1 acts in ribosome-associated quality control of poly(A) translation: by binding the poly(A)-binding protein PABPC1 and associating with polysomes just upstream of poly(A) tails, it promotes ribosome stalling on prematurely polyadenylated (A-rich) messages and ubiquitinates the 40S ribosomal protein RPS10 and PABPC1, positioning it upstream of ZNF598/LTN1 in clearing aberrant nascent chains and preventing production of erroneous proteins.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: MKRN1 ubiquitinates substrate proteins; protein ubiquitination is a core process for this RING E3 ligase. Well supported. Reason: MKRN1 has demonstrated E3 ligase activity (EC 2.3.2.27) and ubiquitinates p53, p21, TERT and ribosome-associated substrates. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function: MKRN1 is a RING-type ubiquitin-protein ligase. Reason: The RING domain confers E3 ligase activity, demonstrated biochemically. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0000209 protein polyubiquitination | IEA GO_REF:0000002 | ACCEPT | Summary: MKRN1 catalyzes polyubiquitination of substrates targeting them for proteasomal degradation. Supported. Reason: MKRN1 mediates proteasome-dependent degradation of p53/p21 via polyubiquitination. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: MKRN1 contains a C3HC4 RING domain and CCCH zinc fingers that coordinate zinc ions. Generic metal-ion binding underlies these structural features. Reason: Zinc coordination by the RING and zinc-finger motifs is structurally required, but the informative functions are E3 ligase activity and RNA binding. Supporting Evidence: file:human/MKRN1/MKRN1-uniprot.txt E3 ubiquitin-protein ligase makorin-1 |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate (electronic) annotation of the core E3 ligase MF. Supported. Reason: Consistent with experimental and phylogenetic evidence for RING E3 ligase activity. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0005515 protein binding | IPI PMID:19536131 Differential regulation of p53 and p21 by MKRN1 E3 ligase co... | KEEP AS NON CORE | Summary: IPI protein-binding annotation from the p53/p21 study. Records substrate interactions but the generic term is uninformative; the E3 ligase MF captures the function. Reason: Substrate binding (p53, p21) is part of E3 ligase function; the generic term is not elevated to core. Supporting Evidence: PMID:19536131 negative regulator of p53 and p21. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Generic protein-binding annotation from a large-scale binary interactome (HuRI). Uninformative as a molecular function. Reason: High-throughput Y2H interactome; no specific functional insight. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic annotation of protein ubiquitination (UniProt keyword mapping). Supported. Reason: Consistent with MKRN1's E3 ligase activity. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0061630 ubiquitin protein ligase activity | TAS Reactome:R-HSA-8948775 | ACCEPT | Summary: Reactome TAS annotation of the core E3 ligase MF. Supported. Reason: Consistent with established RING E3 ligase activity. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:19536131 Differential regulation of p53 and p21 by MKRN1 E3 ligase co... | ACCEPT | Summary: Direct demonstration of MKRN1 ubiquitin-protein ligase activity (in vitro ubiquitination of p53 and p21). Core MF. Reason: Direct biochemical evidence of E3 ligase activity, also reflected in the UniProt catalytic activity (EC 2.3.2.27). Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8948757 | ACCEPT | Summary: Cytosol localization. Consistent with MKRN1's cytoplasmic E3 ligase and ribosome- associated functions. Reason: MKRN1 acts in the cytoplasm on cytosolic substrates and polysomes. Supporting Evidence: PMID:31640799 MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8948775 | ACCEPT | Summary: Duplicate cytosol localization (Reactome TAS). Supported. Reason: MKRN1 is cytoplasmic. Supporting Evidence: PMID:31640799 MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) |
| GO:0000209 protein polyubiquitination | IDA PMID:19536131 Differential regulation of p53 and p21 by MKRN1 E3 ligase co... | ACCEPT | Summary: Direct evidence for MKRN1-mediated polyubiquitination of p53/p21 leading to proteasomal degradation. Supported. Reason: MKRN1 polyubiquitinates substrates for degradation. Supporting Evidence: PMID:19536131 both p53 and p21 through ubiquitination and proteasome-dependent degradation. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | ACCEPT | Summary: RNA binding (mRNA interactome capture). MKRN1 contains CCCH zinc fingers and binds RNA; this underlies its poly(A)-tail recognition in RQC. Genuine and informative. Reason: MKRN1 is an RNA-binding ubiquitin ligase; it binds RNA (including poly(A) regions) and PABPC1 to act co-translationally. Supporting Evidence: PMID:31640799 The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | IMP PMID:31640799 The RNA-binding ubiquitin ligase MKRN1 functions in ribosome... | NEW | Summary: NEW annotation capturing MKRN1's role in ribosome-associated quality control of poly(A) translation. MKRN1 promotes ribosome stalling at poly(A) and ubiquitinates RPS10 and PABPC1, positioning it upstream of ZNF598/LTN1-mediated clearance of aberrant nascent chains. Reason: Direct experimental evidence (iCLIP, ubiquitin-remnant profiling, in vitro ubiquitylation) establishes MKRN1 as an RQC factor for poly(A) translation; this is a core function not yet captured in the GOA set. Supporting Evidence: PMID:31640799 MKRN1 depletion abrogates ribosome stalling at A-rich sequences and results in reduced ubiquitylation of RPS10 and PABPC1. PMID:31640799 The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. |
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Download this section (compressed HTML)Q: How is MKRN1 substrate choice partitioned between its nucleocytoplasmic targets (p53, p21, TERT) and its ribosome-associated RQC substrates (RPS10, PABPC1)?
Q: Is MKRN1's poly(A)-RQC role redundant with or distinct from that of its paralogs MKRN2/3, and how does it interface with ZNF598 and LTN1?
Experiment: Ribosome profiling and ubiquitin-remnant proteomics in MKRN1-knockout versus rescue (RING-dead and RNA-binding-dead mutants) to separate catalytic from RNA-binding contributions to poly(A) stalling.
Experiment: Reconstituted in vitro RQC assays with poly(A)-stalled ribosomes to test the order of MKRN1, ZNF598 and LTN1 ubiquitylation events.
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