mcm-4

UniProt ID: A0A061AL94
Organism: Caenorhabditis elegans
Review Status: DRAFT
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Gene Description

MCM-4 is a subunit of the minichromosome maintenance (MCM2-7) heterohexameric complex, the core replicative DNA helicase in eukaryotes. The MCM2-7 complex is loaded onto replication origins during late mitosis and G1 phase by ORC, Cdc6, and Cdt1 to form the pre-replication complex, licensing origins for a single round of DNA replication per cell cycle. Upon activation at the G1-S transition by CDK and DDK phosphorylation, the MCM2-7 complex associates with Cdc45 and GINS to form the CMG (Cdc45-MCM2-7-GINS) helicase, which unwinds duplex DNA in the 3-prime to 5-prime direction at replication forks during S phase. MCM-4, together with MCM-6 and MCM-7, forms the catalytic MCM4/6/7 core subcomplex that possesses intrinsic DNA helicase activity. MCM-4 contains an AAA+ ATPase domain and a C-terminal winged-helix domain (WHD) involved in DNA binding. Recent structural work identified Mcm4 as a key ATPase during pre-replication complex formation, with Mcm4 ATP hydrolysis triggering Cdt1 release after MCM ring closure. In C. elegans, mcm-4 is expressed in the germ line and in proliferating somatic cells; its expression tracks proliferative competence and is downregulated upon cell cycle exit. CMG helicase function is essential for embryonic cell divisions in C. elegans, and reduced CMG activity causes dramatic increases in cell cycle length. Emerging evidence in C. elegans indicates that the MCM-containing CMG complex also has non-canonical roles in anchor cell invasion and in the divergence of cell fates during asymmetric cell divisions, potentially through replication-coupled epigenetic mechanisms. UniProt accession A0A061AL94 corresponds to transcript Y39G10AR.14b, a short 74 amino acid fragment containing only the C-terminal winged-helix domain (WHD_MCM4, PF21128) of the full-length MCM-4 protein. The canonical full-length C. elegans MCM-4 (P34579) is approximately 860 amino acids.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0003678 DNA helicase activity
ISS
GO_REF:0000024 		NEW
Summary: MCM-4 contributes to DNA helicase activity as part of the MCM4/6/7 catalytic core within the MCM2-7 heterohexameric complex. The MCM4/6/7 subcomplex possesses intrinsic 3-prime to 5-prime DNA helicase activity. MCM-4 does not have independent helicase activity; it contributes to the helicase activity of the complex. This function is well-established across eukaryotes by sequence homology, structural conservation, and biochemical studies of orthologs.
Reason: No GOA annotations exist for this accession. DNA helicase activity is the core molecular function of the MCM4/6/7 subcomplex in which MCM-4 participates, supported by extensive ortholog evidence and domain analysis (WHD_MCM4, PF21128).
Supporting Evidence:
file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
[From deep research] MCM-4 serves a catalytic role within the MCM2-7 replicative helicase complex. The MCM4, MCM6, and MCM7 subunits form a particularly critical MCM4/6/7 core that is essential for helicase function.
GO:0006270 DNA replication initiation
ISS
GO_REF:0000024 		NEW
Summary: MCM-4 is directly involved in DNA replication initiation as a subunit of the MCM2-7 complex, which is loaded onto replication origins during G1 to license them for replication. The MCM2-7 double hexamer is subsequently activated at the G1-S transition to form the CMG helicase that initiates DNA unwinding at origins. Mcm4 ATP hydrolysis is a key step in pre-replication complex formation.
Reason: No GOA annotations exist for this accession. DNA replication initiation is a core biological process for all MCM2-7 subunits, well-established by ortholog studies and functional analysis across eukaryotes.
Supporting Evidence:
file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
[From deep research] Faull et al. (2025) demonstrated that normal helicase loading triggers Mcm4 ATP hydrolysis, which in turn leads to reorganization of the MCM2-7 complex and release of the licensing factor Cdt1.
GO:0006260 DNA replication
ISS
GO_REF:0000024 		NEW
Summary: MCM-4 participates in DNA replication as a subunit of the replicative helicase that unwinds duplex DNA at replication forks during S phase. The CMG complex (Cdc45-MCM2-7-GINS), which includes MCM-4, is the active helicase during replication elongation. In C. elegans, reduced CMG activity causes dramatic increases in cell cycle length, confirming the essential role in replication.
Reason: No GOA annotations exist for this accession. DNA replication is the broader biological process in which MCM-4 functions, both during origin licensing and replication fork progression.
Supporting Evidence:
file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
[From deep research] Memar et al. (2024) ...reducing CMG function causes dramatic increases in cell cycle length in embryonic cells... cell cycle lengths increased from an average of 22 minutes to 39 minutes at early divisions, and from 40 minutes to 144 minutes at later divisions.
GO:0005634 nucleus
ISS
GO_REF:0000024 		NEW
Summary: MCM-4 functions in the nucleus, where the MCM2-7 complex is loaded onto chromatin at replication origins during G1 phase and subsequently operates at replication forks during S phase. In C. elegans, MCM-4::mCherry fusion proteins have been observed associated with chromosomes, consistent with nuclear chromatin-localized function.
Reason: No GOA annotations exist for this accession. Nuclear localization is well-established for MCM complex subunits across eukaryotes. In C. elegans, live-cell imaging confirmed MCM-4 association with chromosomes.
Supporting Evidence:
file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
[From deep research] MCM-4, as part of the MCM2-7 complex, functions in the nucleus on chromatin. The complex is loaded onto chromatin at licensed replication origins during late mitosis and G1 phase.
GO:0042555 MCM complex
ISS
GO_REF:0000024 		NEW
Summary: MCM-4 is a constitutive subunit of the MCM2-7 heterohexameric complex, which is composed of MCM2, MCM3, MCM4, MCM5, MCM6, and MCM7. Within this complex, MCM-4 is part of the catalytic MCM4/6/7 core that possesses the DNA helicase activity. The MCM complex is required for initiation and regulation of DNA replication across all eukaryotes.
Reason: No GOA annotations exist for this accession. MCM-4 is by definition a component of the MCM complex, as established by the protein name, domain composition, and extensive ortholog evidence.

Core Functions

MCM-4 contributes to the DNA helicase activity of the MCM2-7 complex as part of the catalytic MCM4/6/7 core. The MCM2-7 heterohexamer, when activated as part of the CMG complex, unwinds duplex DNA in the 3-prime to 5-prime direction at replication forks. MCM-4 is also a key ATPase during pre-replication complex formation, with Mcm4 ATP hydrolysis triggering ring closure and Cdt1 release. MCM-4 does not possess DNA helicase activity as an isolated subunit; rather, it contributes to the helicase activity of the MCM complex and CMG complex. In C. elegans, CMG function is essential for embryonic cell divisions, and reduced CMG activity causes cell cycle lengths to increase nearly two- to four-fold.

Molecular Function:
DNA helicase activity
Directly Involved In:
DNA replication initiation DNA replication
Cellular Locations:
nucleus
In Complex:
MCM complex
Supporting Evidence:
  • file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
    [From deep research] MCM-4 serves a catalytic role within the MCM2-7 replicative helicase complex. The MCM4, MCM6, and MCM7 subunits form a particularly critical MCM4/6/7 core that is essential for helicase function.
  • file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
    [From deep research] Faull et al. (2025) demonstrated that normal helicase loading triggers Mcm4 ATP hydrolysis, which in turn leads to reorganization of the MCM2-7 complex and release of the licensing factor Cdt1.
  • file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
    [From deep research] MCM-4, as part of the MCM2-7 complex, functions in the nucleus on chromatin. The complex is loaded onto chromatin at licensed replication origins during late mitosis and G1 phase.
  • file:CAEEL/A0A061AL94/A0A061AL94-deep-research-falcon.md
    [From deep research] Memar et al. (2024) ...reducing CMG function causes dramatic increases in cell cycle length in embryonic cells... cell cycle lengths increased from an average of 22 minutes to 39 minutes at early divisions, and from 40 minutes to 144 minutes at later divisions.

References

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Suggested Questions for Experts

Q: Does the short 74 amino acid product of transcript Y39G10AR.14b (A0A061AL94), containing only the C-terminal winged-helix domain of MCM-4, represent a biologically functional protein or is it a non-functional alternative transcript?

Q: What specific roles does C. elegans MCM-4 play in the non-canonical functions of the pre-replication complex, such as anchor cell invasion and asymmetric cell fate determination?

Suggested Experiments

Experiment: Express tagged versions of both the full-length MCM-4 (from Y39G10AR.14a) and the short WHD-only fragment (from Y39G10AR.14b) in C. elegans. Perform co-immunoprecipitation with other MCM subunits to determine whether the short fragment can be incorporated into the MCM2-7 hexamer. Assess subcellular localization by fluorescence microscopy to determine whether the WHD-only fragment localizes to chromatin.

Hypothesis: The 74 AA WHD-only product of Y39G10AR.14b is not incorporated into functional MCM complexes and may not be biologically active.

Type: co-immunoprecipitation and fluorescence microscopy

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · A0A061AL94-protnlm-predictions-review.yaml · Review status: COMPLETE

A0A061AL94 is a 74-residue mcm-4 gene product record. Functions and localization of full-length MCM-4 cannot be assumed to apply intact to this short sequence.

Source documents: genes/CAEEL/A0A061AL94/A0A061AL94-uniprot.txt · genes/CAEEL/A0A061AL94/A0A061AL94-goa.tsv · publications/PMID_21146520.md · genes/CAEEL/A0A061AL94/A0A061AL94-hypotheses/prediction-transcription-initiation/openscientist.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0006367 transcription initiation at RNA polymerase II promoter GO_BP
NPI — Nonparalog incorrect Review score: 0/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
FREQUENCY BIAS
Review rationale: The record links this 74-residue sequence to mcm-4, whose full-length Caenorhabditis elegans product is experimentally established in DNA replication and replication checkpoint control (PMID:21146520). The focused report showed that A0A061AL94 is the isolated C-terminal MCM4 winged-helix fragment and that reviewed full-length MCM4 supports replication terms, not Pol II transcription-initiation terms. The GO:0006367 prediction is best explained as a frequency-biased conflation of winged-helix DNA-binding domains and the word initiation, and is absent from the cached annotations.
Supporting Evidence:
GO:0005634 nucleus GO_CC
UNC — Uncertain Review score: 1/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: Full-length C. elegans MCM-4 associates with chromatin and functions in nuclear DNA replication (PMID:21146520). The accession being evaluated encodes only 74 residues, so transfer of nuclear localization requires evidence that this fragment retains targeting or complex-association determinants or represents an incomplete model of the full-length product. The inspected sources do not resolve that relationship experimentally. Nucleus is absent from the cached annotations and is uncertain for the deposited sequence, despite being appropriate for full-length MCM-4.
Supporting Evidence:

Deep Research

Falcon

(A0A061AL94-deep-research-falcon.md)

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OpenScientist

(A0A061AL94-hypotheses/prediction-transcription-initiation/openscientist.md)

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