MKRN1

UniProt ID: Q9UHC7
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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.

Core Functions

MKRN1 is a RING-type E3 ubiquitin-protein ligase that catalyzes ubiquitin transfer onto substrate lysines, targeting substrates (p53, CDKN1A/p21, TERT, FILIP1, and ribosome- associated RPS10/PABPC1) for regulation or proteasomal degradation.

Molecular Function:
ubiquitin protein ligase activity
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:19536131
    both p53 and p21 through ubiquitination and proteasome-dependent degradation.

As an RNA-binding ubiquitin ligase, MKRN1 binds poly(A)/PABPC1 on polysomes, promotes ribosome stalling on prematurely polyadenylated mRNAs, and ubiquitinates the 40S protein RPS10 and PABPC1 to trigger ribosome-associated quality control of poly(A) translation.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
ribosome-associated ubiquitin-dependent protein catabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:31640799
    MKRN1 depletion abrogates ribosome stalling at A-rich sequences and results in reduced ubiquitylation of RPS10 and PABPC1.

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:19536131
Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis.
  • MKRN1 is an E3 ligase that ubiquitinates p53 and p21 for proteasomal degradation, suppressing p53 under normal conditions and degrading p21 under stress to promote apoptosis.
PMID:22658674
Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
PMID:31640799
The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.
  • MKRN1 binds PABPC1 and polysomes upstream of poly(A) tails, promotes ribosome stalling at A-rich sequences, and ubiquitinates RPS10 and PABPC1, acting in ribosome-associated quality control of poly(A) translation.
PMID:32296183
A reference map of the human binary protein interactome.
Reactome:R-HSA-8948757
Reactome pathway annotation (cytosol localization)
Reactome:R-HSA-8948775
Reactome pathway annotation (MKRN1 ubiquitin ligase activity)
file:human/MKRN1/MKRN1-uniprot.txt
UniProt entry Q9UHC7 (MKRN1_HUMAN)
file:human/MKRN1/MKRN1-goa.tsv
GOA annotations for MKRN1

Suggested Questions for Experts

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?

Suggested Experiments

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.

📚 Additional Documentation

Notes

(MKRN1-notes.md)

MKRN1 (Q9UHC7) research notes

Makorin RING finger protein 1 (RNF61). RING-type E3 ubiquitin ligase with C3HC4 RING and
multiple CCCH/C3H zinc-finger motifs (RNA-binding). Makorin family; paralog MKRN2/3.

Core MF: RING E3 ubiquitin ligase

UniProt: "E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto
substrate proteins." CATALYTIC ACTIVITY EC=2.3.2.27 PMID:19536131.
- Substrates: p53/TP53 (suppresses p53 under normal conditions), CDKN1A/p21 (degrades under
stress, promoting apoptosis), TERT (negative regulator of telomerase), FILIP1.
PMID:19536131
- Direct E3 ligase activity: GO:0061630 (IDA, PMID:19536131); polyubiquitination GO:0000209.

Core BP: ribosome-associated quality control of poly(A) translation

MKRN1 is an RNA-binding E3 that acts in RQC at poly(A) stalls (premature polyadenylation):
PMID:31640799
- Binds PABPC1, associates with polysomes, positioned upstream of poly(A) tails in a PABPC1-
dependent manner; promotes ribosome stalling at poly(A): PMID:31640799
- Ubiquitylates ribosomal protein RPS10 and PABPC1 PMID:31640799
- Acts upstream of ZNF598 (which then ubiquitylates RPS10/RPS20) and LTN1-mediated nascent
chain degradation. This is the RQC role highlighted in the batch instructions.

RNA binding

GO:0003723 RNA binding (HDA, PMID:22658674) — consistent with CCCH zinc fingers and poly(A)
recognition.

Localization

Cytosol (Reactome TAS) — consistent with cytoplasmic E3 / ribosome-associated function.

Annotation plan

  • GO:0061630 ubiquitin protein ligase activity (IBA/IEA/TAS/IDA): ACCEPT (core MF).
  • GO:0016567 protein ubiquitination / GO:0000209 polyubiquitination: ACCEPT.
  • GO:0046872 metal ion binding (IEA): ACCEPT/KEEP_AS_NON_CORE (RING + zinc fingers coordinate Zn).
  • GO:0003723 RNA binding (HDA): ACCEPT (genuine; underlies poly(A) recognition).
  • protein binding IPI (19536131, 32296183): KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED (HT).
  • cytosol TAS: ACCEPT.
  • NEW: GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process and/or
    GO:0072344 rescue of stalled cytosolic ribosome (RQC of poly(A) translation), from PMID:31640799.

Pn Notes

(MKRN1-pn-notes.md)

MKRN1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UHC7
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 11; KEEP_AS_NON_CORE: 3; NEW: 1

PN Consistency Summary

  • Consistency: Strong agreement. Review, notes, deep-research, PN annotation, and PN-node mapping all converge: MKRN1 is a makorin RING E3 ligase (GO:0061630, GO:0016567 — both already in GOA, IDA/IBA) that also acts in poly(A) ribosome-associated QC (PMID:31640799). No contradictions.
  • PN story / NEW pressure: The RQC story IS the value-add and the review already acted on it — it adds GO:1990116 "ribosome-associated ubiquitin-dependent protein catabolic process" as a NEW annotation (IMP, PMID:31640799), verified real and non-obsolete via OLS. This is more specific and more apt than the PN-projected GO:0006515. ADD already done in YAML.
  • Evidence alignment: PN row 2 cites "19489725 / rev" (a makorin review). The review instead anchors on the primary functional papers PMID:19536131 (p53/p21 E3 activity) and PMID:31640799 (poly(A) RQC) — stronger, primary evidence; the PN review-citation is a reasonable family-level pointer not needed in the gene review.
  • Verdict: Consistent; NEW GO:1990116 already correctly added (verified). No edits required; keep gene-level RQC annotation at GO:1990116 rather than the broader PN-projected GO:0006515.

Full Consistency Review

  • UniProt: Q9UHC7 · batch: proteostasis-batch-2026-06-07c · review status: COMPLETE
  • PN placement: two rows — Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination (TR) and UPS|E3 ubiquitin and UBL ligases|RING|Makorin|C3H1-type ZnF (UPS). PN-node mapping: RQC type→GO:0016567 protein ubiquitination (mapped); RQC group→GO:0006515 protein QC for misfolded/incompletely synthesized proteins (mapped); RING group→GO:0061630 ubiquitin protein ligase activity (mapped); Makorin/ZnF subtype + UPS branch = no_mapping.
  • Consistency: Strong agreement. Review, notes, deep-research, PN annotation, and PN-node mapping all converge: MKRN1 is a makorin RING E3 ligase (GO:0061630, GO:0016567 — both already in GOA, IDA/IBA) that also acts in poly(A) ribosome-associated QC (PMID:31640799). No contradictions.
  • PN story / NEW pressure: The RQC story IS the value-add and the review already acted on it — it adds GO:1990116 "ribosome-associated ubiquitin-dependent protein catabolic process" as a NEW annotation (IMP, PMID:31640799), verified real and non-obsolete via OLS. This is more specific and more apt than the PN-projected GO:0006515. ADD already done in YAML.
  • Mapping strategy: No node-mapping change needed. The PN RQC-group projection GO:0006515 is broader than the review's GO:1990116 (a descendant capturing ribosome-associated ubiquitin-dependent catabolism). Per the TOMM20/HSPA8/RAB7A precedent the broader class-projection is acceptable as a group-level node mapping (it spans many RQC members), but for MKRN1 specifically the gene-level annotation should remain the more specific GO:1990116, not GO:0006515. GO:0016567 / GO:0061630 projections are exact and already in GOA.
  • Evidence alignment: PN row 2 cites "19489725 / rev" (a makorin review). The review instead anchors on the primary functional papers PMID:19536131 (p53/p21 E3 activity) and PMID:31640799 (poly(A) RQC) — stronger, primary evidence; the PN review-citation is a reasonable family-level pointer not needed in the gene review.
  • Verdict: Consistent; NEW GO:1990116 already correctly added (verified). No edits required; keep gene-level RQC annotation at GO:1990116 rather than the broader PN-projected GO:0006515.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/MKRN1/MKRN1-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Translation | Cytosolic translation | Ribosome-associated QC | Ubiquitination

  • UniProt: Q9UHC7
  • In branches: TR, UPS
  • PN-node mapping records (path + ancestors):
    • [type] Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0016567 protein ubiquitination]
      rationale: This PN RQC type denotes ubiquitination events on stalled translation complexes. Protein ubiquitination is the shared process target.
    • [group] Translation|Cytosolic translation|Ribosome-associated QC
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
      rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | Makorin | C3H1-type ZnF

  • UniProt: Q9UHC7
  • In branches: TR, UPS
  • Signature domains: IPR001841
  • Auxiliary domains: IPR000571
  • PN references (titles):
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|Makorin|C3H1-type ZnF
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|Makorin
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (3)

  • GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
  • GO:0016567 protein ubiquitination | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Translation|Cytosolic translation|Ribosome-associated QC|Ubiquitination
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

 
id: Q9UHC7
gene_symbol: MKRN1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      MKRN1 ubiquitinates substrate proteins; protein ubiquitination is a core process for
      this RING E3 ligase. Well supported.
    action: ACCEPT
    reason: >-
      MKRN1 has demonstrated E3 ligase activity (EC 2.3.2.27) and ubiquitinates p53, p21,
      TERT and ribosome-associated substrates.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core molecular function: MKRN1 is a RING-type ubiquitin-protein ligase.
    action: ACCEPT
    reason: >-
      The RING domain confers E3 ligase activity, demonstrated biochemically.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      MKRN1 catalyzes polyubiquitination of substrates targeting them for proteasomal
      degradation. Supported.
    action: ACCEPT
    reason: >-
      MKRN1 mediates proteasome-dependent degradation of p53/p21 via polyubiquitination.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      MKRN1 contains a C3HC4 RING domain and CCCH zinc fingers that coordinate zinc ions.
      Generic metal-ion binding underlies these structural features.
    action: KEEP_AS_NON_CORE
    reason: >-
      Zinc coordination by the RING and zinc-finger motifs is structurally required, but the
      informative functions are E3 ligase activity and RNA binding.
    supported_by:
    - reference_id: file:human/MKRN1/MKRN1-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase makorin-1
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Duplicate (electronic) annotation of the core E3 ligase MF. Supported.
    action: ACCEPT
    reason: >-
      Consistent with experimental and phylogenetic evidence for RING E3 ligase activity.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19536131
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Substrate binding (p53, p21) is part of E3 ligase function; the generic term is not
      elevated to core.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: negative regulator of p53 and p21.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Generic protein-binding annotation from a large-scale binary interactome (HuRI). Uninformative as a molecular function.
    action: KEEP_AS_NON_CORE
    reason: >-
      High-throughput Y2H interactome; no specific functional insight.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation of protein ubiquitination (UniProt keyword mapping). Supported.
    action: ACCEPT
    reason: >-
      Consistent with MKRN1's E3 ligase activity.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948775
  qualifier: enables
  review:
    summary: >-
      Reactome TAS annotation of the core E3 ligase MF. Supported.
    action: ACCEPT
    reason: >-
      Consistent with established RING E3 ligase activity.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:19536131
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of MKRN1 ubiquitin-protein ligase activity (in vitro
      ubiquitination of p53 and p21). Core MF.
    action: ACCEPT
    reason: >-
      Direct biochemical evidence of E3 ligase activity, also reflected in the UniProt
      catalytic activity (EC 2.3.2.27).
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948757
  qualifier: located_in
  review:
    summary: >-
      Cytosol localization. Consistent with MKRN1's cytoplasmic E3 ligase and ribosome-
      associated functions.
    action: ACCEPT
    reason: >-
      MKRN1 acts in the cytoplasm on cytosolic substrates and polysomes.
    supported_by:
    - reference_id: PMID:31640799
      supporting_text: MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1)
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8948775
  qualifier: located_in
  review:
    summary: >-
      Duplicate cytosol localization (Reactome TAS). Supported.
    action: ACCEPT
    reason: >-
      MKRN1 is cytoplasmic.
    supported_by:
    - reference_id: PMID:31640799
      supporting_text: MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1)
- term:
    id: GO:0000209
    label: protein polyubiquitination
  evidence_type: IDA
  original_reference_id: PMID:19536131
  qualifier: involved_in
  review:
    summary: >-
      Direct evidence for MKRN1-mediated polyubiquitination of p53/p21 leading to
      proteasomal degradation. Supported.
    action: ACCEPT
    reason: >-
      MKRN1 polyubiquitinates substrates for degradation.
    supported_by:
    - reference_id: PMID:19536131
      supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- term:
    id: GO:0003723
    label: RNA binding
  evidence_type: HDA
  original_reference_id: PMID:22658674
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      MKRN1 is an RNA-binding ubiquitin ligase; it binds RNA (including poly(A) regions) and
      PABPC1 to act co-translationally.
    supported_by:
    - reference_id: PMID:31640799
      supporting_text: The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.
- term:
    id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:31640799
  qualifier: involved_in
  review:
    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.
    action: NEW
    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.
    supported_by:
    - reference_id: PMID:31640799
      supporting_text: MKRN1 depletion abrogates ribosome stalling at A-rich sequences and results in reduced ubiquitylation of RPS10 and PABPC1.
    - reference_id: PMID:31640799
      supporting_text: The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.
core_functions:
- description: >-
    MKRN1 is a RING-type E3 ubiquitin-protein ligase that catalyzes ubiquitin transfer onto
    substrate lysines, targeting substrates (p53, CDKN1A/p21, TERT, FILIP1, and ribosome-
    associated RPS10/PABPC1) for regulation or proteasomal degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:19536131
    supporting_text: both p53 and p21 through ubiquitination and proteasome-dependent degradation.
- description: >-
    As an RNA-binding ubiquitin ligase, MKRN1 binds poly(A)/PABPC1 on polysomes, promotes
    ribosome stalling on prematurely polyadenylated mRNAs, and ubiquitinates the 40S protein
    RPS10 and PABPC1 to trigger ribosome-associated quality control of poly(A) translation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:31640799
    supporting_text: MKRN1 depletion abrogates ribosome stalling at A-rich sequences and results in reduced ubiquitylation of RPS10 and PABPC1.
  directly_involved_in:
  - id: GO:1990116
    label: ribosome-associated ubiquitin-dependent protein catabolic process
proposed_new_terms: []
suggested_questions:
- question: How is MKRN1 substrate choice partitioned between its nucleocytoplasmic targets (p53, p21, TERT) and its ribosome-associated RQC substrates (RPS10, PABPC1)?
- question: 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?
suggested_experiments:
- description: 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.
- description: Reconstituted in vitro RQC assays with poly(A)-stalled ribosomes to test the order of MKRN1, ZNF598 and LTN1 ubiquitylation events.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:19536131
  title: Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis.
  findings:
  - statement: MKRN1 is an E3 ligase that ubiquitinates p53 and p21 for proteasomal degradation, suppressing p53 under normal conditions and degrading p21 under stress to promote apoptosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches the YAML title and GOA anchors this PMID to IDA for GO:0061630 (ubiquitin protein ligase activity) and GO:0000209; establishes MKRN1's core E3 ligase function on p53/p21.
- id: PMID:22658674
  title: Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
  findings: []
- id: PMID:31640799
  title: The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.
  findings:
  - statement: MKRN1 binds PABPC1 and polysomes upstream of poly(A) tails, promotes ribosome stalling at A-rich sequences, and ubiquitinates RPS10 and PABPC1, acting in ribosome-associated quality control of poly(A) translation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached publication title matches the YAML title and content describes MKRN1 binding PABPC1/polysomes and ubiquitinating RPS10/PABPC1; establishes the RNA-binding ubiquitin-ligase role in poly(A) RQC.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: Reactome:R-HSA-8948757
  title: Reactome pathway annotation (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8948775
  title: Reactome pathway annotation (MKRN1 ubiquitin ligase activity)
  findings: []
- id: file:human/MKRN1/MKRN1-uniprot.txt
  title: UniProt entry Q9UHC7 (MKRN1_HUMAN)
  findings: []
- id: file:human/MKRN1/MKRN1-goa.tsv
  title: GOA annotations for MKRN1
  findings: []