Affinage

DONSON

Protein downstream neighbor of Son · UniProt Q9NYP3

Length
566 aa
Mass
62.7 kDa
Annotated
2026-06-09
23 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DONSON is a metazoan replication factor that operates at the heart of the cell cycle by driving assembly and stabilization of the replicative CMG helicase (PMID:28191891, PMID:37781960). At replication initiation it scaffolds a vertebrate pre-loading complex containing GINS, TOPBP1, and DNA polymerase ε, engaging these partners through its conserved N-terminal PGY and NPF motifs, and docks this complex onto MCM2-7 to deliver GINS during CMG (CDC45-MCM-GINS) assembly (PMID:37590370, PMID:37458194). This activity is gated by cell-cycle kinases: DONSON's chromatin loading requires the pre-replicative complex and TOPBP1, and both S-CDK and DDK depend on DONSON to trigger initiation, with DONSON binding TOPBP1 in a CDK-dependent manner (PMID:37458194, PMID:37638758). DONSON binds CDC45-MCM-GINS transiently during S phase and is dispensable for G1 MCM2-7 loading but essential for S-phase helicase activation (PMID:37781960). Structurally, a DONSON dimer bridges two CMG complexes and reconfigures the MCM motors, and patient mutations that disrupt dimerization impair GINS/MCM engagement and DNA synthesis (PMID:37820732). Beyond initiation, DONSON persists as a replisome component that stabilizes forks, prevents nucleolytic cleavage of stalled forks, and supports ATR-dependent checkpoint signaling, with DONSON-bound replisomes preferentially associating with early-replicating euchromatin (PMID:28191891, PMID:32769987, PMID:37638758). DONSON is essential for proliferating progenitors, including telencephalic neuroepithelium, and biallelic loss-of-function or localization-disrupting mutations cause microcephalic dwarfism syndromes including Meier-Gorlin syndrome (PMID:28630177, PMID:31784481, PMID:33739968, PMID:37590370).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2017 High

    Established DONSON as a genome-stability factor by linking it to replisome function and fork protection, answering whether the gene had a direct role in replication rather than a peripheral one.

    Evidence Patient biallelic mutation identification with replication fork and ATR checkpoint assays in DONSON-deficient cells

    PMID:28191891

    Open questions at the time
    • Did not define the molecular step DONSON catalyzes at the fork
    • No direct biochemical partner identified
  2. 2017 Medium

    Placed DONSON within the proliferating-progenitor and replication-factor expression program and showed it is essential for development, framing why its loss produces growth/brain phenotypes.

    Evidence Human brain RNA-seq co-expression analysis and Donson mouse embryonic lethality

    PMID:28630177

    Open questions at the time
    • Correlative co-expression, not a direct mechanistic role
    • Lethality stage does not pinpoint the affected cell-cycle step
  3. 2019 Medium

    Showed that Meier-Gorlin-associated missense variants converge on disrupted nuclear localization, establishing that nuclear access is a functional requirement.

    Evidence Whole genome sequencing and nuclear localization assays of variants in patient-derived cells

    PMID:31784481

    Open questions at the time
    • Localization signal/mechanism of nuclear import not mapped
    • Functional consequence inferred from phenotype, not biochemistry
  4. 2020 High

    Distinguished two replisome populations by chromatin domain and timing, showing DONSON-bound replisomes are an early-S/euchromatin-associated class.

    Evidence iPOND combined with ChIP-seq and replication timing analysis

    PMID:32769987

    Open questions at the time
    • Does not explain what specifies DONSON to early-replicating regions
    • Functional consequence of the two populations unresolved
  5. 2021 High

    Defined the cell-type basis of the neurological phenotype, showing DONSON is required in telencephalic neuroepithelial progenitors.

    Evidence Conditional Cre-driver knockout mice with histology and apoptosis assays

    PMID:33739968

    Open questions at the time
    • Does not connect progenitor loss to a specific replication defect at molecular resolution
  6. 2023 High

    Resolved DONSON's core mechanism: it scaffolds a pre-loading complex (GINS, TOPBP1, Pol ε) and delivers GINS to MCM2-7 to assemble CMG, defining it as an initiation factor and explaining the dwarfism phenotype.

    Evidence AlphaFold-guided interaction screening with Co-IP/pulldown validation, CMG assembly assays, and patient-mutation knock-in mice; corroborated by Xenopus cell-free reconstitution mapping PGY/NPF motifs and S-CDK/DDK dependence; degron depletion separating G1 from S-phase roles

    PMID:37458194 PMID:37590370 PMID:37638758 PMID:37781960

    Open questions at the time
    • Precise order of GINS handoff and motor engagement not fully resolved
    • Mechanism coupling initiation role to later fork-protection role unclear
  7. 2023 High

    Provided structural mechanism: a DONSON dimer bridges two CMG complexes and reconfigures MCM motors, and dimerization-disrupting patient mutations impair helicase engagement and DNA synthesis.

    Evidence Cryo-EM of native double-CMG complexes from Xenopus egg extracts with dimerization-interface mutagenesis and validation in human cells and Xenopus extracts

    PMID:37820732

    Open questions at the time
    • Functional purpose of the double-CMG configuration in vivo not fully defined
    • Whether dimerization is required at every origin is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DONSON's transient initiation-stage helicase-assembly role is mechanistically linked to its persistent elongation-stage fork-protection and ATR-signaling functions remains unresolved.
  • No mechanism connecting CMG assembly to fork stabilization
  • Determinants of DONSON-replisome targeting to early euchromatin unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 1
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-69306 DNA Replication 3 R-HSA-1640170 Cell Cycle 2 R-HSA-8953897 Cellular responses to stimuli 1
Partners
CDC45GINSMCM2-7POLETOPBP1
Complex memberships
CMG helicasedouble CMGpre-loading complex (pre-LC)replisome

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 DONSON is a replisome component that stabilizes replication forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage from nucleolytic cleavage of stalled replication forks, and ATR-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and chromosomal instability. Genetic identification of biallelic mutations in patients, cell-based replication assays, DNA damage marker analysis, ATR signaling assays in DONSON-deficient cells Nature genetics High 28191891
2017 DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, co-expressed with components of the DNA replication machinery, and Donson is essential for early embryonic development in mice, indicating an essential conserved role in the cell cycle. RNA-seq transcriptome analysis, aberrant splicing detection, mouse embryonic lethality upon Donson disruption, co-expression analysis with replication factors Genome research Medium 28630177
2019 Missense variants in DONSON associated with Meier-Gorlin syndrome all disrupted the nuclear localization of DONSON, establishing that proper nuclear localization is required for DONSON function. Linked-read whole genome sequencing, nuclear localization assays of missense variants in patient-derived cells Journal of medical genetics Medium 31784481
2020 DONSON-bound replisomes are more frequent in early S phase and associate with euchromatin regions, whereas FANCM-bound replisomes predominate in late S phase and heterochromatin, identifying two distinct replisome populations distinguished by chromatin domain and replication timing. iPOND (isolation of proteins on nascent DNA), ChIP-seq of DONSON- and FANCM-associated DNA, replication timing analysis Nature communications High 32769987
2021 Conditional deletion of Donson in progenitors of cortical glutamatergic neurons (Emx1-Cre) caused extensive apoptosis in the early dorsomedial neuroepithelium, preventing formation of the neocortex and hippocampus. Deletion in subpallial progenitors (Nkx2.1-Cre) ablated 75% of Nkx2.1-derived cortical GABAergic neurons, establishing Donson as essential for early telencephalic neuroepithelium progenitors. Conditional knockout mouse models (Emx1-Cre, Tbr2-Cre, Nkx2.1-Cre), histology, immunofluorescence, apoptosis assays PLoS genetics High 33739968
2023 DONSON scaffolds a vertebrate pre-loading complex (pre-LC) containing GINS, TOPBP1, and DNA pol ε, and docks this pre-LC onto MCM2-7 to deliver GINS to its binding site during CMG helicase assembly at replication initiation. A patient-derived DONSON mutation compromises CMG assembly and recapitulates microcephalic dwarfism in mice. AlphaFold-based protein-protein interaction screening followed by experimental validation (Co-IP, pulldown), mouse patient-mutation knock-in model, CMG assembly assays Science (New York, N.Y.) High 37590370
2023 DONSON is required for CMG (CDC45-MCM-GINS) helicase assembly during S-phase in mammalian cells. DONSON binds directly but transiently to CDC45-MCM-GINS during S-phase and is dispensable for MCM2-7 loading onto chromatin during G1-phase, but essential for CDC45-MCM-GINS assembly during S-phase. Rapid protein depletion (auxin-inducible degron) in mouse embryonic stem cells, co-immunoprecipitation, chromatin fractionation, S-phase specific helicase assembly assays EMBO reports High 37781960
2023 DONSON is essential for replisome assembly in vertebrates. DONSON physically interacts with GINS and Pol ε via its conserved N-terminal PGY and NPF motifs. DONSON's chromatin association during replication initiation requires the pre-replicative complex, TopBP1, and kinase activities of S-CDK and DDK. Both S-CDK and DDK require DONSON to trigger replication initiation. Xenopus laevis cell-free replication system, immunodepletion/add-back experiments, co-immunoprecipitation, motif mutagenesis (PGY and NPF motifs), kinase inhibitor experiments The EMBO journal High 37458194
2023 DONSON is required for Cdc45 and GINS association with Mcm2-7 complexes and helicase activation during replication initiation. DONSON interacts with the initiation factor TopBP1 in a CDK-dependent manner. Following initiation, DONSON also forms part of the replisome during the elongation stage of DNA replication. Xenopus laevis egg extract cell-free system, immunodepletion, co-immunoprecipitation, chromatin association assays, CDK inhibitor experiments Nucleic acids research High 37638758
2023 Cryo-EM of proteins from replicating Xenopus egg extracts identified a double CMG complex bridged by a DONSON dimer. DONSON dimerization reconfigures the MCM motors in the double CMG. Tethering elements mediating complex formation are essential for replication, and primordial dwarfism patient mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts. Cryo-electron microscopy (cryo-EM) of native complexes from Xenopus egg extracts, mutagenesis of dimerization interface, human cell complementation assays, Xenopus DNA synthesis assays Molecular cell High 37820732

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Circular RNA circ-DONSON facilitates gastric cancer growth and invasion via NURF complex dependent activation of transcription factor SOX4. Molecular cancer 204 30922402
2017 Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism. Nature genetics 96 28191891
2023 In silico protein interaction screening uncovers DONSON's role in replication initiation. Science (New York, N.Y.) 89 37590370
2017 Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome research 39 28630177
2020 CircRNA DONSON contributes to cisplatin resistance in gastric cancer cells by regulating miR-802/BMI1 axis. Cancer cell international 38 32581651
2020 DONSON and FANCM associate with different replisomes distinguished by replication timing and chromatin domain. Nature communications 36 32769987
2023 The structural mechanism of dimeric DONSON in replicative helicase activation. Molecular cell 35 37820732
2019 Linked-read genome sequencing identifies biallelic pathogenic variants in DONSON as a novel cause of Meier-Gorlin syndrome. Journal of medical genetics 34 31784481
2023 Novel role of DONSON in CMG helicase assembly during vertebrate DNA replication initiation. The EMBO journal 32 37458194
2023 DONSON facilitates Cdc45 and GINS chromatin association and is essential for DNA replication initiation. Nucleic acids research 29 37638758
2000 Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes. Genomics 28 10950926
2023 DONSON is required for CMG helicase assembly in the mammalian cell cycle. EMBO reports 22 37781960
2019 Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities. American journal of medical genetics. Part A 19 31407851
2021 Circ-DONSON Knockdown Inhibits Cell Proliferation and Radioresistance of Breast Cancer Cells via Regulating SOX4. Journal of oncology 11 34853591
2021 Circ-DONSON Facilitates the Malignant Progression of Gastric Cancer Depending on the Regulation of miR-149-5p/LDHA Axis. Biochemical genetics 10 34409524
2022 Microcephalic primordial dwarfism with predominant Meier-Gorlin phenotype, ichthyosis, and multiple joint deformities-Further expansion of DONSON Cell Cycle-opathy phenotypic spectrum. American journal of medical genetics. Part A 8 35298084
2020 Downstream neighbor of SON (DONSON) is associated with unfavorable survival across diverse cancers with oncogenic properties in clear cell renal cell carcinoma. Translational oncology 7 32805676
2020 Downstream Neighbor of SON (DONSON) Expression Is Enhanced in Phenotypically Aggressive Prostate Cancers. Cancers 7 33228112
2023 DONSON: Slding in 2 the limelight. DNA repair 6 38159447
2020 Circ-DONSON promotes malignant progression of glioma through modulating FOXO3. European review for medical and pharmacological sciences 6 32016978
2019 Further Delineation of the Microcephaly-Micromelia Syndrome Associated with Loss-of-Function Variants in DONSON. Molecular syndromology 5 31191207
2021 The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons. PLoS genetics 1 33739968
2026 Meier-Gorlin syndrome due to a recurrent DONSON variant in a Turkish family: first report of thumb aplasia and long-term growth data. Journal of pediatric endocrinology & metabolism : JPEM 0 41612845

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