{"gene":"MRC1","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2003,"finding":"Yeast Tof1 and Mrc1 interact directly with the DNA replication machinery and form a stable replication-pausing complex at arrested forks in S. cerevisiae, demonstrated by their co-precipitation with replication fork components during hydroxyurea-induced arrest.","method":"Co-immunoprecipitation with replication fork components; chromatin immunoprecipitation during HU arrest","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and ChIP at replication forks, replicated by multiple subsequent labs","pmids":["12944972"],"is_preprint":false},{"year":2001,"finding":"S. cerevisiae Mrc1 (mediator of replication checkpoint) is required for activation of Rad53 kinase in response to DNA replication stress (hydroxyurea); mrc1 mutants show checkpoint defects similar to rad53 mutants.","method":"Genetic deletion (mrc1Δ), checkpoint kinase activation assays, HU sensitivity","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined checkpoint phenotype, independently replicated in two papers (S. cerevisiae and S. pombe) in the same issue","pmids":["11715016"],"is_preprint":false},{"year":2001,"finding":"Fission yeast Mrc1 associates with Cds1 kinase and is required for Rad3-dependent activation of Cds1 specifically during S phase; Mrc1 protein appears coinciding with S phase.","method":"Yeast two-hybrid (Mrc1-Cds1 association), genetic deletion, cell-cycle expression analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — physical interaction plus loss-of-function phenotype, replicated independently in S. pombe alongside S. cerevisiae findings","pmids":["11715017"],"is_preprint":false},{"year":2003,"finding":"S. cerevisiae Mrc1 is present at replication forks, moves with the fork during S phase, and requires active replication initiation for its loading onto origins. Mec1-dependent phosphorylation of Mrc1 at canonical SQ/TQ motifs is required for Rad53 activation but not for Mrc1's role in DNA replication.","method":"Chromatin immunoprecipitation (ChIP) to track Mrc1 at origins and forks; phosphorylation-site mutagenesis; checkpoint activation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP tracking plus mutagenesis separating replication and checkpoint functions, rigorous controls","pmids":["12865299"],"is_preprint":false},{"year":2004,"finding":"Fission yeast Mrc1 contains an ~150 amino acid DNA-binding domain (DBD) in its N-terminal region that preferentially binds branched DNA structures in vitro; mutations in the DBD impair replication checkpoint arrest and HU resistance. This DBD contains a helix-loop-helix motif conserved with human Claspin.","method":"In vitro DNA-binding assays with purified domain; point mutagenesis; HU sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of DNA binding with mutagenesis, single lab but orthogonal methods","pmids":["15471884"],"is_preprint":false},{"year":2004,"finding":"Fission yeast Mrc1 is required for initial Thr11 phosphorylation of Cds1 by Rad3-Rad26; Mrc1 interacts with the FHA domain of Cds1, and this interaction recruits Cds1 to Rad3-Rad26 for phosphorylation.","method":"Yeast two-hybrid (Mrc1-Cds1 FHA domain interaction); FHA domain point mutations; in vivo Thr11 phosphorylation assays; Rad26-Cds1 fusion rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of interaction domain, fusion rescue, multiple orthogonal methods in single study","pmids":["15173168"],"is_preprint":false},{"year":2003,"finding":"Fission yeast Mrc1 is phosphorylated by Rad3 and Tel1 at two S/TQ clusters; phosphorylation of T645 mediates FHA-domain-dependent interaction with Cds1 and is required for HU resistance; phosphorylation of the S604-containing cluster promotes increased chromatin association of Mrc1 in replication-arrested cells.","method":"Phosphorylation-site mutagenesis (S/TQ→AQ); electrophoretic mobility shift assays; yeast two-hybrid; chromatin association assays; rad3Δ tel1Δ double mutant analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis of multiple sites with functional readouts, multiple orthogonal methods","pmids":["14585996"],"is_preprint":false},{"year":2005,"finding":"S. cerevisiae Mrc1 is required for normal replication fork progression rate and for fork recovery after HU-induced stalling, independently of Rad53. Tof1 is critical for rDNA replication fork barrier activity but plays a minor role in the replication checkpoint, while Mrc1 is essential for the checkpoint but not for RFB activity.","method":"2D gel electrophoresis of replication intermediates; genetic deletion (mrc1Δ, tof1Δ, rad53 mutants); HU release experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — 2D gel analysis of fork intermediates plus genetic epistasis, replicated with multiple alleles","pmids":["16137625"],"is_preprint":false},{"year":2005,"finding":"Fission yeast Mrc1/Tof1/Csm3 checkpoint complex interacts directly with the MCM helicase during both normal fork progression and stalled forks, coupling replicative unwinding to DNA synthesis.","method":"Biochemical co-immunoprecipitation; genetic synthetic lethality with polymerase alpha/primase mutants; plasmid supercoiling assay as readout of uncoupled unwinding","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing direct interaction with MCM, single lab with two methods","pmids":["15755447"],"is_preprint":false},{"year":2007,"finding":"S. cerevisiae Mrc1 strongly reduces the rate of DNA replication fork progression; loss of Mrc1 greatly slows forks while loss of Tof1 has less effect on speed but abolishes pausing at protein-DNA barriers.","method":"DNA combing (single-molecule replication tracking); genetic deletion strains","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative single-molecule DNA combing, clear functional phenotype, replicated in context of prior biochemical work","pmids":["17652453"],"is_preprint":false},{"year":2008,"finding":"S. cerevisiae Mrc1 interacts with both the N-terminal (Pol2N) and C-terminal (Pol2C) halves of Pol2, the catalytic subunit of DNA polymerase epsilon. Mrc1 phosphorylation during the S-phase checkpoint abolishes Pol2N binding but not Pol2C interaction, and Mrc1 is required to stabilize Pol2 at stalled forks.","method":"Co-immunoprecipitation; chromatin immunoprecipitation; phosphorylation-dependent interaction analysis using Mrc1 phosphomutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus ChIP, phosphorylation-dependent dissection of two distinct binding interactions","pmids":["18851837"],"is_preprint":false},{"year":2009,"finding":"S. cerevisiae Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that co-associates with moving replication forks; both Tof1 and Csm3 are required for Mrc1 association with the fork, while deletion of mrc1 does not affect Tof1/Csm3 association. Baculovirus co-expression confirmed direct protein-protein interactions.","method":"ChIP-on-chip; baculovirus coexpression and co-immunoprecipitation of purified proteins; genetic deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein reconstitution in baculovirus system plus ChIP epistasis, multiple orthogonal methods","pmids":["19819872"],"is_preprint":false},{"year":2009,"finding":"Fission yeast Swi1-Swi3 complex physically interacts with Mrc1 and synergistically facilitates Mrc1 DNA binding in vitro; Mrc1 preferentially binds arrested fork or D-loop structures, and the Swi1-Swi3 complex enhances this affinity by forming a ternary complex. Mutations in the Mrc1 DNA-binding domain abolish both the interaction and the synergistic effect.","method":"Purified protein DNA-binding assays (EMSA/gel shift); co-immunoprecipitation of purified proteins; mutagenesis of Mrc1 DNA-binding domain and Swi1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis, multiple orthogonal binding assays","pmids":["20924116"],"is_preprint":false},{"year":2009,"finding":"S. cerevisiae Mrc1 directly binds Mcm6 via the central coiled-coil region of Mrc1 interacting with the 168 aa C-terminal region of Mcm6; this interaction is required for checkpoint activation specifically in response to methyl methanesulfonate (MMS) but not HU treatment. Physical fusion of Mcm6 mutant with Mrc1 rescued the MMS checkpoint defect.","method":"Co-immunoprecipitation; mutagenesis of Mcm6 C-terminus; Mcm6-Mrc1 fusion rescue experiment; checkpoint activation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis plus fusion rescue provides strong mechanistic evidence, multiple orthogonal approaches","pmids":["19620285"],"is_preprint":false},{"year":2009,"finding":"Purified Mrc1 cooperates with Mec1 to activate Rad53 in vitro; Mrc1 facilitates Rad53 phosphorylation by promoting a stronger Mec1-Rad53 enzyme-substrate interaction (~70-fold stimulation), and the conserved C-terminal domain of Mrc1 is required for this activity.","method":"In vitro reconstitution with purified Mec1 and Mrc1; activity-based kinase assay for Rad53; C-terminal domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified proteins, domain deletion, quantitative kinase assay","pmids":["19457865"],"is_preprint":false},{"year":2009,"finding":"Mec1-dependent phosphorylation of Mrc1 (independent of Rad53) is required for stabilization of Mec1 at stalled forks via a positive feedback loop; a central region of Mrc1 is required for mediator function and replisome association.","method":"Structure-function analysis of Mrc1 alleles; ChIP of Mec1 at stalled forks; genetic epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP epistasis plus domain analysis, single lab","pmids":["19515819"],"is_preprint":false},{"year":2004,"finding":"Mrc1 in S. cerevisiae is required for sister chromatid cohesion established at the replication fork; mrc1Δ mutants have sister chromatid cohesion defects independent of checkpoint function; synthetic lethality of srs2Δ mrc1Δ is due to inappropriate recombination and depends on Mrc1's replicative but not checkpoint function.","method":"Synthetic genetic array; sister chromatid cohesion assay; suppression by recombination mutants; checkpoint-defective allele analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with defined suppression, cohesion assay, separation of function alleles","pmids":["15282308"],"is_preprint":false},{"year":2009,"finding":"S. cerevisiae mrc1Δ suppresses homologous recombination at DNA double-strand breaks in an Mrc1-dependent manner; the replication checkpoint suppresses formation of Rad52 foci and impedes resection of DNA ends. Mrc1 does not prevent recombination at stalled forks (which already contain ssDNA).","method":"Rad52 foci quantification; HO endonuclease-induced DSB recombination assays; genetic epistasis with mrc1Δ and checkpoint mutants","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative recombination assays with genetic epistasis, single lab","pmids":["19322196"],"is_preprint":false},{"year":2006,"finding":"Fission yeast Swi1 and Swi3 are required for chromatin association of Mrc1; Mrc1 interacts with Swi3 and with Hsk1 kinase through its central SQ/TQ-containing segment; Hsk1 stabilizes Mrc1 protein levels through phosphorylation of a potential phosphodegron.","method":"Co-immunoprecipitation; chromatin fractionation; deletion analysis mapping interaction domains","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP interaction mapping, chromatin association assays, single lab","pmids":["19422421"],"is_preprint":false},{"year":2021,"finding":"In vitro reconstitution with purified proteins shows Rad53 phosphorylation of Mrc1 slows DNA replication fork elongation by preventing Mrc1-stimulated CMG helicase unwinding; Mrc1 stimulates CMG unwinding rate, and Rad53-phosphorylated Mrc1 cannot stimulate replication. Phosphorylation of Sld3/7 or Dbf4-CDK blocks initiation, while Mrc1 phosphorylation is necessary and sufficient to slow elongation.","method":"In vitro DNA replication reconstitution with purified proteins; helicase unwinding assays; phosphomimetic Mrc1 mutant analysis in vitro and in vivo","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted in vitro replication system with purified components, phosphomimetic mutagenesis, multiple orthogonal readouts","pmids":["34387546"],"is_preprint":false},{"year":2024,"finding":"Fission yeast Mrc1 promotes transfer of parental histone H3-H4 to the lagging strand and facilitates interaction between Mcm2 and DNA polymerase alpha, supporting heterochromatin inheritance. This function is independent of Mrc1's checkpoint and replisome speed roles; Mrc1 interacts with Mcm2 outside its histone-binding region.","method":"Genetic analysis; co-immunoprecipitation; chromatin immunoprecipitation; separation-of-function alleles; heterochromatin inheritance assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — separation-of-function alleles demonstrating independent mechanism, Co-IP, functional heterochromatin assay, multiple orthogonal methods","pmids":["39094566"],"is_preprint":false},{"year":2020,"finding":"S. cerevisiae Sen1 transcription termination helicase associates with replisomes via direct binding to Ctf4 and Mrc1 at the N-terminus of Sen1; a separation-of-function mutant (sen1-3) that abolishes replisome binding without affecting transcription termination causes increased genome instability.","method":"Co-immunoprecipitation; separation-of-function mutant analysis; genome instability assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP mapping interaction, separation-of-function mutant with defined phenotype, single lab","pmids":["32075754"],"is_preprint":false},{"year":2018,"finding":"S. cerevisiae Mrc1 and Rad9 control DNA replication through two distinct mechanisms in response to DNA damage: Mrc1 rapidly activates Rad53 at stalled forks and represses late-firing origins, while Rad9 takes over to maintain continuous checkpoint signaling and slows fork progression.","method":"Genetic epistasis (mrc1Δ, rad9Δ double mutants); DNA replication and fork rate analysis; Rad53 activation kinetics","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with functional readouts of origin firing and fork rate, single lab","pmids":["30158111"],"is_preprint":false},{"year":2018,"finding":"N-terminal phosphorylation of S. cerevisiae Mrc1 by multiple stress-activated kinases (identified by unbiased kinome screening) blocks replication and prevents transcription-associated recombination during stress-induced transcriptional outbursts in S phase, defining a general safeguard mechanism against transcription-replication conflicts.","method":"Unbiased kinome screening; phosphorylation site mutagenesis; recombination assays; genetic analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinome screen plus mutagenesis identifying specific phosphorylation sites, functional recombination readout, single lab","pmids":["29371596"],"is_preprint":false},{"year":2006,"finding":"Fission yeast Tel2 is required for efficient phosphorylation of Mrc1 and subsequent activation of Cds1 in response to hydroxyurea-induced replication block; Tel2 acts upstream of Mrc1 in the replication checkpoint pathway.","method":"Genetic epistasis (tel2 repression in mrc1Δ and cds1Δ backgrounds); Mrc1 phosphorylation assays; checkpoint activation analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis and phosphorylation assays placing Tel2 upstream of Mrc1, single lab","pmids":["17189249"],"is_preprint":false},{"year":2016,"finding":"S. cerevisiae Rtt101Mms22 E3 ubiquitin ligase associates with the replisome via Ctf4 and counteracts Mrc1's replicative function; mrc1Δ rtt101Δ double mutants complete DNA replication under stress via a Rad52-dependent mechanism, indicating Rtt101Mms22 does not degrade Mrc1 but specifically antagonizes its replicative role at stalled forks.","method":"Interactome mass spectrometry (Mms22 IP-MS); suppressor screen; genetic double-mutant analysis; Rad52 epistasis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus genetic epistasis with functional suppression, single lab","pmids":["26849847"],"is_preprint":false},{"year":2011,"finding":"Fission yeast Mrc1 selectively binds early-firing replication origins independently of Cdc45 and Hsk1 kinase before S phase; in mrc1Δ cells, early origins (those normally Mrc1-bound) fire precociously and with higher efficiency, while late origins are unaffected. This origin-timing function requires the non-checkpoint activity of Mrc1.","method":"ChIP-on-chip (genome-wide Mrc1 binding); replication timing analysis; checkpoint-defective mrc1 allele comparison","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP with separation-of-function alleles demonstrating origin-specific regulation independent of checkpoint function","pmids":["21518960"],"is_preprint":false},{"year":2010,"finding":"Deletion of MRC1 in S. cerevisiae maintains wild-type origin firing times despite >2-fold lengthening of S phase, whereas 13 other slow-S-phase mutants all showed proportional scaling of the entire replication timing program; mrc1Δ also activates numerous dormant origins.","method":"Genome-wide replication timing analysis by DNA microarray; genetic screen of 14 S-phase mutants","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide analysis distinguishing MRC1's unique role, single lab comparative screen","pmids":["20219942"],"is_preprint":false},{"year":2006,"finding":"S. cerevisiae Mrc1 plays a specific role in DNA replication that promotes Srs2 recruitment to PCNA independently of checkpoint signaling, thereby preventing crossover formation; mrc1Δ increases spontaneous crossover rates comparably to srs2Δ.","method":"Genetic screen for spontaneous crossover rates; epistasis analysis with srs2Δ, mrc1Δ, and pol30-RR (PCNA) mutants","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with quantitative crossover assay identifying non-checkpoint replication function, single lab","pmids":["16724109"],"is_preprint":false},{"year":2007,"finding":"S. cerevisiae Mrc1 protects uncapped telomeres (cdc13-1 and yku70Δ backgrounds) from Exo1-dependent nucleolytic degradation; protection is due to Mrc1's replicative function (not checkpoint function), as the checkpoint-defective mrc1AQ allele behaves like wild-type at telomeres.","method":"Genetic deletion analysis; mrc1AQ separation-of-function allele; single-stranded DNA accumulation assays; EXO1 epistasis","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — separation-of-function allele plus nuclease epistasis, defined molecular phenotype","pmids":["17618841"],"is_preprint":false},{"year":2019,"finding":"S. cerevisiae Mrc1's fork-stabilizing function (but not checkpoint activation function) is required to prevent DNA breakage and cell death at long CAG repeats; both functions contribute to preventing repeat length instability.","method":"Separation-of-function mrc1 alleles; DNA breakage assays; repeat instability assays; genetic analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — separation-of-function alleles with distinct phenotypic readouts for breakage vs. instability","pmids":["30476303"],"is_preprint":false},{"year":1992,"finding":"The human MRC1 gene encoding the macrophage mannose receptor is divided into 30 exons; the first three encode the signal sequence, N-terminal cysteine-rich domain, and fibronectin type II repeat; the final exon encodes the transmembrane anchor and cytoplasmic tail; the intervening 26 exons encode the eight carbohydrate-recognition domains.","method":"Genomic cloning and sequencing of the entire MRC1 coding region; exon-intron boundary mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic sequencing of entire gene locus, foundational structural characterization","pmids":["1294118"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of MRC1/CD206 C-type carbohydrate-recognition domain 4 (CRD4) in complex with mannose, GlcNAc, fucose, Manα1-2Man disaccharide, and Lewis-a trisaccharide reveal Ca2+-dependent binding mechanisms: mannose and GlcNAc engage equatorial 3- and 4-OH groups with the principal Ca2+; fucose can bind in multiple orientations; the Manα1-2Man disaccharide gains additional affinity through contacts with the reducing mannose residue.","method":"Glycan array screening; multiple crystal structures of CRD4-ligand complexes; isothermal titration calorimetry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures with distinct ligands plus functional glycan array data, rigorous structural and binding analysis","pmids":["33545173"],"is_preprint":false},{"year":2018,"finding":"Pneumolysin (PLY) from S. pneumoniae binds directly to MRC1/CD206 on human dendritic cells and mouse alveolar macrophages, suppressing pro-inflammatory cytokine responses and TLR signaling, upregulating SOCS1, mediating pneumococcal internalization into non-lysosomal compartments, and polarizing T cells toward an immunoregulatory phenotype. MRC1-deficient mice show reduced bacterial loads in the airways.","method":"Direct binding assay (PLY-MRC1); MRC1 knockout mouse infection model; blocking antibody experiments; cytokine/signaling assays in dendritic cells and macrophages","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding plus receptor KO in vivo phenotype plus multiple cellular mechanistic readouts","pmids":["30420782"],"is_preprint":false},{"year":2011,"finding":"MRC1/CD206 promotes ricin toxin binding and uptake into monocytes in vitro, and MRC1-knockout mice are significantly more susceptible to ricin-induced death in vivo, indicating MRC1 functions in scavenging/degradation of ricin rather than facilitating its toxicity.","method":"In vitro ricin binding and uptake assays; MRC1 knockout mouse challenge with ricin (2.5× and 5× LD50)","journal":"Toxins","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assays plus KO mouse in vivo phenotype, single lab","pmids":["22069759"],"is_preprint":false},{"year":2002,"finding":"CD206/MRC1 on inflammatory dendritic epidermal cells (IDECs) mediates receptor-mediated endocytosis of mannosylated antigens (dextran-FITC uptake), whereas Langerhans cells that lack CD206 do not show this CD206-dependent endocytosis.","method":"Flow cytometry; dextran-FITC uptake assay; electron microscopy with immunogold staining; pinocytosis control (Lucifer yellow)","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-mediated endocytosis assay with specific inhibition, defined cellular localization by EM","pmids":["11841552"],"is_preprint":false},{"year":2013,"finding":"Cockroach allergen Bla g 2 (which bears mannose-terminated N-glycans) binds directly to CD206/MRC1 on human fibrocytes, and this interaction mediates allergen uptake and activation of NF-κB, p38, ERK, and JNK signaling pathways, leading to TNF-α and IL-6 production; all these effects are blocked by mannan or anti-CD206 antibody.","method":"MALDI-MS N-glycan profiling; solid-phase binding assay; antibody blocking; FITC-allergen uptake by fibrocytes; intracellular signaling (kinase phosphorylation) and cytokine assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay plus functional signaling readouts with specific blocking, single lab","pmids":["23734186"],"is_preprint":false},{"year":2018,"finding":"Galectin-9 binds directly to CD206 on macrophages (Kd ~2.8 × 10^-7 M; confirmed by immunoprecipitation and blocked by anti-CD206), and this interaction induces CD206+ macrophages to produce more FGF2 and MCP-1 but less MDC, supporting a tumor-promoting microenvironment.","method":"Immunoprecipitation of CD206-galectin-9 complex from cell lysates; competition binding assay; fluorescence anisotropy for affinity measurement; cytokine secretion assays","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus fluorescence anisotropy affinity measurement and functional cytokine readout, single lab","pmids":["29732570"],"is_preprint":false},{"year":2022,"finding":"Sulfated galactose glycopolymers (SO4-3-Gal) targeting the cysteine-rich domain of CD206 block receptor function by forming stable intracellular CD206-glycopolymer complexes that prevent receptor recycling to the cell membrane, both in vitro and in vivo in mice.","method":"Endocytosis and receptor recycling assays; in vitro CD206 activity assays; in vivo administration in mice; intracellular complex characterization","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with defined molecular mechanism of receptor blockade, single lab","pmids":["36472883"],"is_preprint":false},{"year":2021,"finding":"MRC1/CD206 CTLD4-7 is highly selective for pauci- and oligomannose N-glycans (among hundreds of glycans tested on glycan arrays); tumor cells and A549 lung cancer cells express MRC1-binding ligands carrying these glycans, identified by immunoprecipitation and glycoproteomics.","method":"Glycan microarray screening; flow cytometry; immunoprecipitation of MR-Fc from cancer cell lysates; glycoproteomic analysis (42 proteins identified)","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — glycan array and glycoproteomics with functional binding validation, single lab","pmids":["34089345"],"is_preprint":false},{"year":2020,"finding":"RP-182 selectively activates CD206 on human and murine M2-like macrophages, inducing a conformational switch that triggers endocytosis, phagosome-lysosome formation, and autophagy, and reprograms M2-like tumor-associated macrophages to an M1-like antitumor phenotype.","method":"In vitro macrophage functional assays (endocytosis, phagosome formation); murine syngeneic/autochthonous tumor models; CD206high PDX models","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assays demonstrating CD206-mediated signaling program, in vivo validation, single lab","pmids":["32051227"],"is_preprint":false},{"year":2017,"finding":"CD206/MRC1+ M2-like macrophages in adipose tissue inhibit adipocyte progenitor proliferation via TGF-β1 secretion and TGF-β signaling; ablation of CD206+ M2-like macrophages in transgenic mice increases smaller adipocyte numbers, reduces TGF-β signaling, and improves systemic insulin sensitivity.","method":"CD206-diphtheria toxin receptor transgenic mouse depletion model; adipocyte progenitor proliferation assays; TGF-β signaling pathway analysis; adipose tissue phenotyping","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional CD206+ cell depletion with defined molecular pathway (TGF-β) and phenotypic readout, single lab","pmids":["28819169"],"is_preprint":false},{"year":2022,"finding":"CD206+ M2-like macrophages inhibit FAP-derived follistatin secretion via TGF-β1 signaling; depletion of CD206+ macrophages or deletion of macrophage-specific TGF-β1 activates FAPs to secrete follistatin, promoting myogenesis and muscle regeneration. FAP-specific follistatin deletion impairs muscle stem cell function.","method":"CD206-DTR transgenic mouse depletion; macrophage-specific TGF-β1 gene deletion; FAP isolation and follistatin secretion assays; muscle regeneration phenotyping","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic depletion + tissue-specific gene deletion identifying TGF-β1 as the molecular effector, single lab","pmids":["36411280"],"is_preprint":false},{"year":2015,"finding":"Mesenchymal stem cells (UCMSCs) promote CD206 expression and phagocytic activity in macrophages through IL-6 in a mouse SLE model and in vitro with human SLE macrophages; IL-6 blockade abrogates the UCMSC-mediated increase in CD206 expression and phagocytosis.","method":"UCMSC-macrophage co-culture; IL-6 neutralization; flow cytometry; phagocytosis assays in vitro and in vivo","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IL-6 required for CD206 upregulation shown by blocking experiment, in vitro and in vivo confirmation, single lab","pmids":["26209923"],"is_preprint":false},{"year":2012,"finding":"Colocalization of Mec1 (via Ddc2-LacI) and Mrc1-LacI at LacO arrays in S. cerevisiae is sufficient to activate Rad53 phosphorylation; this minimal replication checkpoint signal is independent of Ddc1 and Dpb11 (Mec1 activators required for DNA damage checkpoint).","method":"LacI-LacO tethering system (in vivo replication checkpoint mimic); Rad53 phosphorylation assays; genetic epistasis with ddc1Δ, dpb11, mrc1Δ","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthetic tethering system with defined genetic requirements, single lab","pmids":["22298423"],"is_preprint":false}],"current_model":"MRC1 encodes two functionally distinct proteins: (1) in yeast (canonical replication checkpoint protein), Mrc1/Claspin is a replisome-associated mediator that travels with replication forks, directly binds Mcm6 and Pol2 (DNA polymerase epsilon), stimulates CMG helicase unwinding rate, facilitates Mec1-dependent phosphorylation and Rad53 activation via a solid-state platform at stalled forks, and promotes parental histone H3-H4 transfer to the lagging strand for epigenetic inheritance—all separable from its checkpoint function; (2) in mammals, MRC1/CD206 is a transmembrane C-type lectin on macrophages/dendritic cells whose CRD4 mediates Ca2+-dependent binding to mannose, fucose, GlcNAc, and oligomannose glycans (structurally defined by crystal structures), enabling receptor-mediated endocytosis of pathogens and glycoproteins, direct binding of ligands including pneumolysin (suppressing inflammation) and galectin-9 (promoting pro-tumor cytokines), and paracrine signaling via TGF-β1 that regulates adipocyte progenitor proliferation and muscle regeneration."},"narrative":{"mechanistic_narrative":"The MRC1 symbol maps to two molecularly distinct, internally coherent proteins in this corpus, and the timeline supports both pictures independently. In yeast, Mrc1 (mediator of the replication checkpoint, the Claspin ortholog) is a replisome-associated factor that travels with the replication fork and couples fork progression to checkpoint signaling [PMID:12944972, PMID:12865299]. It loads at early-firing origins before S phase and constrains their timing and efficiency independently of checkpoint function [PMID:21518960], and as part of a heterotrimeric Csm3-Tof1-Mrc1 mediator complex it associates with moving forks, with Tof1/Csm3 required for Mrc1 fork association [PMID:19819872]. Mrc1 directly engages the replicative helicase and polymerase—binding Mcm6 through its central coiled-coil [PMID:19620285] and both halves of the Pol epsilon catalytic subunit Pol2 [PMID:18851837]—and stimulates the CMG helicase to set normal fork elongation rate [PMID:17652453, PMID:34387546]. In its checkpoint role, Mec1/Rad3-Tel1-dependent phosphorylation at S/TQ clusters licenses Mrc1 to bridge Mec1 to Rad53/Cds1 as an enzyme-substrate platform, accelerating Rad53 activation ~70-fold via its conserved C-terminal domain [PMID:12865299, PMID:19457865, PMID:22298423]; in fission yeast this requires Mrc1 binding the Cds1 FHA domain [PMID:15173168, PMID:14585996]. Checkpoint and replicative functions are cleanly separable by mutation: the replicative arm supports sister chromatid cohesion, suppression of inappropriate recombination, telomere protection, and parental histone H3-H4 transfer to the lagging strand for heterochromatin inheritance, all independent of Rad53 signaling [PMID:16137625, PMID:15282308, PMID:17618841, PMID:39094566]. Rad53-mediated phosphorylation of Mrc1 in turn slows fork elongation by blocking its CMG-stimulating activity, integrating checkpoint feedback into replication speed [PMID:34387546]. The mammalian protein MRC1/CD206 is structurally and functionally unrelated: a transmembrane macrophage/dendritic-cell C-type lectin organized into a cysteine-rich domain, fibronectin type II repeat, and eight carbohydrate-recognition domains [PMID:1294118], whose CRD4 mediates Ca2+-dependent recognition of mannose, GlcNAc, fucose, and oligomannose glycans as defined by crystal structures [PMID:33545173, PMID:34089345]. It functions as an endocytic receptor for mannosylated antigens and pathogen ligands [PMID:11841552], binding pneumolysin to suppress inflammation [PMID:30420782] and galectin-9 to drive a pro-tumor cytokine program [PMID:29732570], and CD206+ M2-like macrophages signal through TGF-β1 to regulate adipocyte progenitor proliferation and muscle regeneration [PMID:28819169, PMID:36411280].","teleology":[{"year":2001,"claim":"Established that Mrc1 is a dedicated mediator of the DNA replication checkpoint, defining a Rad53/Cds1-activating function distinct from the DNA damage checkpoint.","evidence":"mrc1Δ deletion with checkpoint kinase activation assays in budding yeast, and Cds1 association/S-phase-specific activation in fission yeast","pmids":["11715016","11715017"],"confidence":"High","gaps":["Did not resolve whether Mrc1 acts at forks or globally","Molecular mechanism of Rad53/Cds1 activation unknown at this stage"]},{"year":2003,"claim":"Showed Mrc1 physically travels with the replisome and that its checkpoint phosphorylation is separable from its replication role, the first separation-of-function evidence.","evidence":"ChIP tracking of Mrc1 at origins/forks, co-IP with fork components during HU arrest, and SQ/TQ phosphosite mutagenesis","pmids":["12944972","12865299"],"confidence":"High","gaps":["Direct replisome binding partners not yet mapped","How Mec1 phosphorylates Mrc1 at the fork undefined"]},{"year":2004,"claim":"Identified the structural basis for Mrc1-DNA engagement and for recruiting the effector kinase, linking fork-structure sensing to checkpoint signaling.","evidence":"in vitro DNA-binding assays of an N-terminal HLH domain preferring branched DNA, plus Cds1 FHA-domain interaction mapping and cohesion/recombination genetics","pmids":["15471884","15173168","15282308"],"confidence":"High","gaps":["In vivo relevance of branched-DNA binding not fully established","Cohesion mechanism (idx 16) Medium confidence and single-lab"]},{"year":2005,"claim":"Defined Mrc1's role in setting fork progression rate and coupling helicase unwinding to synthesis, distinguishing it from Tof1's pausing function.","evidence":"2D gel analysis of replication intermediates, genetic epistasis, and MCM helicase co-IP with supercoiling readout in fission yeast","pmids":["16137625","15755447"],"confidence":"High","gaps":["Direct mechanism of helicase coupling not biochemically reconstituted at this stage","MCM interaction (idx 8) Medium confidence"]},{"year":2009,"claim":"Reconstituted the mediator architecture: Mrc1 directly binds Mcm6 and Pol2 within a Csm3-Tof1-Mrc1 complex and cooperates with Mec1 to activate Rad53, providing the biochemical platform model.","evidence":"baculovirus co-expression/co-IP of purified complex, Mcm6 and Pol2 interaction mapping with fusion-rescue, and in vitro Mec1-Mrc1-Rad53 kinase reconstitution","pmids":["19819872","19620285","18851837","19457865","19515819"],"confidence":"High","gaps":["Stoichiometry of the platform at forks unresolved","How phosphorylation toggles Pol2N vs Pol2C binding mechanistically unclear"]},{"year":2011,"claim":"Revealed a checkpoint-independent role in controlling replication origin timing and efficiency, showing Mrc1 selectively marks and restrains early origins.","evidence":"genome-wide ChIP-on-chip of Mrc1 binding and replication timing analysis with checkpoint-defective alleles in fission and budding yeast","pmids":["21518960","20219942"],"confidence":"High","gaps":["Molecular mechanism by which Mrc1 restrains early origin firing undefined","Connection between origin binding and fork-traveling pool unclear"]},{"year":2021,"claim":"Provided the definitive mechanism for checkpoint-replication integration: Mrc1 stimulates CMG unwinding rate, and Rad53 phosphorylation of Mrc1 abolishes this to slow elongation.","evidence":"fully reconstituted in vitro replication with purified components, helicase assays, and phosphomimetic Mrc1 mutants in vitro and in vivo","pmids":["34387546"],"confidence":"High","gaps":["Whether phospho-regulation of CMG stimulation occurs at every fork or selectively unknown","Structural basis of CMG stimulation not solved"]},{"year":2024,"claim":"Added an epigenetic inheritance function, showing Mrc1 routes parental H3-H4 histones to the lagging strand independently of its checkpoint and speed roles.","evidence":"separation-of-function alleles, co-IP showing Mcm2/Pol-alpha facilitation, and heterochromatin inheritance assays in fission yeast","pmids":["39094566"],"confidence":"High","gaps":["Mechanism of strand-biased histone deposition not fully defined","Conservation of this role in mammals untested in this corpus"]},{"year":1992,"claim":"Established the domain architecture of the unrelated mammalian MRC1/CD206 mannose receptor, defining its eight carbohydrate-recognition domains and membrane topology.","evidence":"genomic cloning and exon-intron mapping of the full human MRC1 locus","pmids":["1294118"],"confidence":"High","gaps":["Glycan specificity of individual CRDs not defined","No structural data at this stage"]},{"year":2021,"claim":"Defined the structural and glycan-recognition basis of CD206, showing CRD4 binds mannose, GlcNAc, fucose, and oligomannose via Ca2+-dependent contacts with selectivity for pauci-/oligomannose N-glycans.","evidence":"multiple CRD4-ligand crystal structures, ITC, and glycan-array/glycoproteomic profiling of tumor-cell ligands","pmids":["33545173","34089345"],"confidence":"High","gaps":["Functional contributions of the other CRDs underexplored","Physiological endogenous ligand repertoire incomplete"]},{"year":2018,"claim":"Demonstrated CD206 as an endocytic and immunomodulatory receptor for pathogen and self ligands, linking glycan recognition to inflammation control and disease.","evidence":"direct pneumolysin and galectin-9 binding, MRC1-knockout mouse infection phenotype, and cytokine/signaling readouts in macrophages and dendritic cells","pmids":["30420782","29732570","23734186","11841552","22069759"],"confidence":"Medium","gaps":["Signaling pathway downstream of CD206 ligand engagement incompletely mapped","Most cellular mechanism studies are single-lab Medium confidence"]},{"year":2022,"claim":"Established CD206+ M2-like macrophages as TGF-β1-secreting paracrine regulators of tissue homeostasis and as actionable targets for receptor manipulation.","evidence":"CD206-DTR depletion and macrophage-specific TGF-β1 deletion in mice (adipose and muscle), plus CD206-targeting glycopolymer and agonist (RP-182) functional studies","pmids":["36411280","28819169","32051227","36472883"],"confidence":"Medium","gaps":["Direct receptor-proximal signaling distinct from cell-population effects not fully resolved","TGF-β1 regulation downstream of CD206 itself not mechanistically dissected"]},{"year":null,"claim":"It remains unresolved how the separable yeast Mrc1/Claspin functions (checkpoint platform, CMG stimulation, origin timing, histone inheritance) are coordinated at a single fork, and whether the mammalian Claspin ortholog performs these roles; the two MRC1 proteins in this corpus share no demonstrated functional relationship.","evidence":"no timeline discovery bridges the yeast replication protein and the human CD206 lectin","pmids":[],"confidence":"Low","gaps":["No human Claspin replication data in this corpus","Symbol collision means the two protein narratives must be kept distinct"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,13,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14,19]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[33,35]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[35,34,39]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,3,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,26]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[31,33,35]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[35,38]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[0,3,9,19]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[1,14,44]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[22,26]},{"term_id":"R-HSA-4839726","term_label":"Chromatin 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Binds both sulfated and non-sulfated polysaccharide chains (Microbial infection) Acts as a phagocytic receptor for bacteria, fungi and other pathogens (Microbial infection) Acts as a receptor for Dengue virus envelope protein E (Microbial infection) Interacts with Hepatitis B virus envelope protein","subcellular_location":"Endosome membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P22897/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MRC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MRC1","total_profiled":1310},"omim":[{"mim_id":"620302","title":"WD REPEAT-CONTAINING PROTEIN 76; WDR76","url":"https://www.omim.org/entry/620302"},{"mim_id":"618101","title":"MATRIX METALLOPROTEINASE 27; MMP27","url":"https://www.omim.org/entry/618101"},{"mim_id":"614372","title":"MANNOSE-BINDING LECTIN DEFICIENCY; MBLD","url":"https://www.omim.org/entry/614372"},{"mim_id":"612264","title":"MANNOSE RECEPTOR, C-TYPE, 2; MRC2","url":"https://www.omim.org/entry/612264"},{"mim_id":"609461","title":"TRIBBLES PSEUDOKINASE 1; TRIB1","url":"https://www.omim.org/entry/609461"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lung","ntpm":115.2}],"url":"https://www.proteinatlas.org/search/MRC1"},"hgnc":{"alias_symbol":["CLEC13D","CD206","bA541I19.1","CLEC13DL"],"prev_symbol":["MRC1L1"]},"alphafold":{"accession":"P22897","domains":[{"cath_id":"2.80.10.50","chopping":"26-155","consensus_level":"high","plddt":88.72,"start":26,"end":155},{"cath_id":"2.10.10.10","chopping":"159-178_185-220","consensus_level":"medium","plddt":87.8595,"start":159,"end":220},{"cath_id":"3.10.100.10","chopping":"225-343","consensus_level":"high","plddt":84.834,"start":225,"end":343},{"cath_id":"3.10.100.10","chopping":"368-490","consensus_level":"high","plddt":89.6984,"start":368,"end":490},{"cath_id":"3.10.100.10","chopping":"523-629","consensus_level":"high","plddt":89.7173,"start":523,"end":629},{"cath_id":"3.10.100.10","chopping":"659-781","consensus_level":"high","plddt":85.0883,"start":659,"end":781},{"cath_id":"3.10.100.10","chopping":"806-931","consensus_level":"high","plddt":82.102,"start":806,"end":931},{"cath_id":"3.10.100.10","chopping":"951-1083","consensus_level":"high","plddt":86.7401,"start":951,"end":1083},{"cath_id":"3.10.100.10","chopping":"1101-1216","consensus_level":"high","plddt":87.6767,"start":1101,"end":1216}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22897","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22897-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22897-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRC1","jax_strain_url":"https://www.jax.org/strain/search?query=MRC1"},"sequence":{"accession":"P22897","fasta_url":"https://rest.uniprot.org/uniprotkb/P22897.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22897/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22897"}},"corpus_meta":[{"pmid":"12944972","id":"PMC_12944972","title":"S-phase 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Mec1-dependent phosphorylation of Mrc1 at canonical SQ/TQ motifs is required for Rad53 activation but not for Mrc1's role in DNA replication.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) to track Mrc1 at origins and forks; phosphorylation-site mutagenesis; checkpoint activation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP tracking plus mutagenesis separating replication and checkpoint functions, rigorous controls\",\n      \"pmids\": [\"12865299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fission yeast Mrc1 contains an ~150 amino acid DNA-binding domain (DBD) in its N-terminal region that preferentially binds branched DNA structures in vitro; mutations in the DBD impair replication checkpoint arrest and HU resistance. This DBD contains a helix-loop-helix motif conserved with human Claspin.\",\n      \"method\": \"In vitro DNA-binding assays with purified domain; point mutagenesis; HU sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of DNA binding with mutagenesis, single lab but orthogonal methods\",\n      \"pmids\": [\"15471884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fission yeast Mrc1 is required for initial Thr11 phosphorylation of Cds1 by Rad3-Rad26; Mrc1 interacts with the FHA domain of Cds1, and this interaction recruits Cds1 to Rad3-Rad26 for phosphorylation.\",\n      \"method\": \"Yeast two-hybrid (Mrc1-Cds1 FHA domain interaction); FHA domain point mutations; in vivo Thr11 phosphorylation assays; Rad26-Cds1 fusion rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of interaction domain, fusion rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"15173168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Fission yeast Mrc1 is phosphorylated by Rad3 and Tel1 at two S/TQ clusters; phosphorylation of T645 mediates FHA-domain-dependent interaction with Cds1 and is required for HU resistance; phosphorylation of the S604-containing cluster promotes increased chromatin association of Mrc1 in replication-arrested cells.\",\n      \"method\": \"Phosphorylation-site mutagenesis (S/TQ→AQ); electrophoretic mobility shift assays; yeast two-hybrid; chromatin association assays; rad3Δ tel1Δ double mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis of multiple sites with functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"14585996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"S. cerevisiae Mrc1 is required for normal replication fork progression rate and for fork recovery after HU-induced stalling, independently of Rad53. Tof1 is critical for rDNA replication fork barrier activity but plays a minor role in the replication checkpoint, while Mrc1 is essential for the checkpoint but not for RFB activity.\",\n      \"method\": \"2D gel electrophoresis of replication intermediates; genetic deletion (mrc1Δ, tof1Δ, rad53 mutants); HU release experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — 2D gel analysis of fork intermediates plus genetic epistasis, replicated with multiple alleles\",\n      \"pmids\": [\"16137625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fission yeast Mrc1/Tof1/Csm3 checkpoint complex interacts directly with the MCM helicase during both normal fork progression and stalled forks, coupling replicative unwinding to DNA synthesis.\",\n      \"method\": \"Biochemical co-immunoprecipitation; genetic synthetic lethality with polymerase alpha/primase mutants; plasmid supercoiling assay as readout of uncoupled unwinding\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing direct interaction with MCM, single lab with two methods\",\n      \"pmids\": [\"15755447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S. cerevisiae Mrc1 strongly reduces the rate of DNA replication fork progression; loss of Mrc1 greatly slows forks while loss of Tof1 has less effect on speed but abolishes pausing at protein-DNA barriers.\",\n      \"method\": \"DNA combing (single-molecule replication tracking); genetic deletion strains\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative single-molecule DNA combing, clear functional phenotype, replicated in context of prior biochemical work\",\n      \"pmids\": [\"17652453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"S. cerevisiae Mrc1 interacts with both the N-terminal (Pol2N) and C-terminal (Pol2C) halves of Pol2, the catalytic subunit of DNA polymerase epsilon. Mrc1 phosphorylation during the S-phase checkpoint abolishes Pol2N binding but not Pol2C interaction, and Mrc1 is required to stabilize Pol2 at stalled forks.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation; phosphorylation-dependent interaction analysis using Mrc1 phosphomutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus ChIP, phosphorylation-dependent dissection of two distinct binding interactions\",\n      \"pmids\": [\"18851837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S. cerevisiae Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that co-associates with moving replication forks; both Tof1 and Csm3 are required for Mrc1 association with the fork, while deletion of mrc1 does not affect Tof1/Csm3 association. Baculovirus co-expression confirmed direct protein-protein interactions.\",\n      \"method\": \"ChIP-on-chip; baculovirus coexpression and co-immunoprecipitation of purified proteins; genetic deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein reconstitution in baculovirus system plus ChIP epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"19819872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fission yeast Swi1-Swi3 complex physically interacts with Mrc1 and synergistically facilitates Mrc1 DNA binding in vitro; Mrc1 preferentially binds arrested fork or D-loop structures, and the Swi1-Swi3 complex enhances this affinity by forming a ternary complex. Mutations in the Mrc1 DNA-binding domain abolish both the interaction and the synergistic effect.\",\n      \"method\": \"Purified protein DNA-binding assays (EMSA/gel shift); co-immunoprecipitation of purified proteins; mutagenesis of Mrc1 DNA-binding domain and Swi1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, mutagenesis, multiple orthogonal binding assays\",\n      \"pmids\": [\"20924116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S. cerevisiae Mrc1 directly binds Mcm6 via the central coiled-coil region of Mrc1 interacting with the 168 aa C-terminal region of Mcm6; this interaction is required for checkpoint activation specifically in response to methyl methanesulfonate (MMS) but not HU treatment. Physical fusion of Mcm6 mutant with Mrc1 rescued the MMS checkpoint defect.\",\n      \"method\": \"Co-immunoprecipitation; mutagenesis of Mcm6 C-terminus; Mcm6-Mrc1 fusion rescue experiment; checkpoint activation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis plus fusion rescue provides strong mechanistic evidence, multiple orthogonal approaches\",\n      \"pmids\": [\"19620285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Purified Mrc1 cooperates with Mec1 to activate Rad53 in vitro; Mrc1 facilitates Rad53 phosphorylation by promoting a stronger Mec1-Rad53 enzyme-substrate interaction (~70-fold stimulation), and the conserved C-terminal domain of Mrc1 is required for this activity.\",\n      \"method\": \"In vitro reconstitution with purified Mec1 and Mrc1; activity-based kinase assay for Rad53; C-terminal domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified proteins, domain deletion, quantitative kinase assay\",\n      \"pmids\": [\"19457865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mec1-dependent phosphorylation of Mrc1 (independent of Rad53) is required for stabilization of Mec1 at stalled forks via a positive feedback loop; a central region of Mrc1 is required for mediator function and replisome association.\",\n      \"method\": \"Structure-function analysis of Mrc1 alleles; ChIP of Mec1 at stalled forks; genetic epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP epistasis plus domain analysis, single lab\",\n      \"pmids\": [\"19515819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mrc1 in S. cerevisiae is required for sister chromatid cohesion established at the replication fork; mrc1Δ mutants have sister chromatid cohesion defects independent of checkpoint function; synthetic lethality of srs2Δ mrc1Δ is due to inappropriate recombination and depends on Mrc1's replicative but not checkpoint function.\",\n      \"method\": \"Synthetic genetic array; sister chromatid cohesion assay; suppression by recombination mutants; checkpoint-defective allele analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with defined suppression, cohesion assay, separation of function alleles\",\n      \"pmids\": [\"15282308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"S. cerevisiae mrc1Δ suppresses homologous recombination at DNA double-strand breaks in an Mrc1-dependent manner; the replication checkpoint suppresses formation of Rad52 foci and impedes resection of DNA ends. Mrc1 does not prevent recombination at stalled forks (which already contain ssDNA).\",\n      \"method\": \"Rad52 foci quantification; HO endonuclease-induced DSB recombination assays; genetic epistasis with mrc1Δ and checkpoint mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative recombination assays with genetic epistasis, single lab\",\n      \"pmids\": [\"19322196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fission yeast Swi1 and Swi3 are required for chromatin association of Mrc1; Mrc1 interacts with Swi3 and with Hsk1 kinase through its central SQ/TQ-containing segment; Hsk1 stabilizes Mrc1 protein levels through phosphorylation of a potential phosphodegron.\",\n      \"method\": \"Co-immunoprecipitation; chromatin fractionation; deletion analysis mapping interaction domains\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP interaction mapping, chromatin association assays, single lab\",\n      \"pmids\": [\"19422421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In vitro reconstitution with purified proteins shows Rad53 phosphorylation of Mrc1 slows DNA replication fork elongation by preventing Mrc1-stimulated CMG helicase unwinding; Mrc1 stimulates CMG unwinding rate, and Rad53-phosphorylated Mrc1 cannot stimulate replication. Phosphorylation of Sld3/7 or Dbf4-CDK blocks initiation, while Mrc1 phosphorylation is necessary and sufficient to slow elongation.\",\n      \"method\": \"In vitro DNA replication reconstitution with purified proteins; helicase unwinding assays; phosphomimetic Mrc1 mutant analysis in vitro and in vivo\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted in vitro replication system with purified components, phosphomimetic mutagenesis, multiple orthogonal readouts\",\n      \"pmids\": [\"34387546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Fission yeast Mrc1 promotes transfer of parental histone H3-H4 to the lagging strand and facilitates interaction between Mcm2 and DNA polymerase alpha, supporting heterochromatin inheritance. This function is independent of Mrc1's checkpoint and replisome speed roles; Mrc1 interacts with Mcm2 outside its histone-binding region.\",\n      \"method\": \"Genetic analysis; co-immunoprecipitation; chromatin immunoprecipitation; separation-of-function alleles; heterochromatin inheritance assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — separation-of-function alleles demonstrating independent mechanism, Co-IP, functional heterochromatin assay, multiple orthogonal methods\",\n      \"pmids\": [\"39094566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S. cerevisiae Sen1 transcription termination helicase associates with replisomes via direct binding to Ctf4 and Mrc1 at the N-terminus of Sen1; a separation-of-function mutant (sen1-3) that abolishes replisome binding without affecting transcription termination causes increased genome instability.\",\n      \"method\": \"Co-immunoprecipitation; separation-of-function mutant analysis; genome instability assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP mapping interaction, separation-of-function mutant with defined phenotype, single lab\",\n      \"pmids\": [\"32075754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"S. cerevisiae Mrc1 and Rad9 control DNA replication through two distinct mechanisms in response to DNA damage: Mrc1 rapidly activates Rad53 at stalled forks and represses late-firing origins, while Rad9 takes over to maintain continuous checkpoint signaling and slows fork progression.\",\n      \"method\": \"Genetic epistasis (mrc1Δ, rad9Δ double mutants); DNA replication and fork rate analysis; Rad53 activation kinetics\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with functional readouts of origin firing and fork rate, single lab\",\n      \"pmids\": [\"30158111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"N-terminal phosphorylation of S. cerevisiae Mrc1 by multiple stress-activated kinases (identified by unbiased kinome screening) blocks replication and prevents transcription-associated recombination during stress-induced transcriptional outbursts in S phase, defining a general safeguard mechanism against transcription-replication conflicts.\",\n      \"method\": \"Unbiased kinome screening; phosphorylation site mutagenesis; recombination assays; genetic analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinome screen plus mutagenesis identifying specific phosphorylation sites, functional recombination readout, single lab\",\n      \"pmids\": [\"29371596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Fission yeast Tel2 is required for efficient phosphorylation of Mrc1 and subsequent activation of Cds1 in response to hydroxyurea-induced replication block; Tel2 acts upstream of Mrc1 in the replication checkpoint pathway.\",\n      \"method\": \"Genetic epistasis (tel2 repression in mrc1Δ and cds1Δ backgrounds); Mrc1 phosphorylation assays; checkpoint activation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis and phosphorylation assays placing Tel2 upstream of Mrc1, single lab\",\n      \"pmids\": [\"17189249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"S. cerevisiae Rtt101Mms22 E3 ubiquitin ligase associates with the replisome via Ctf4 and counteracts Mrc1's replicative function; mrc1Δ rtt101Δ double mutants complete DNA replication under stress via a Rad52-dependent mechanism, indicating Rtt101Mms22 does not degrade Mrc1 but specifically antagonizes its replicative role at stalled forks.\",\n      \"method\": \"Interactome mass spectrometry (Mms22 IP-MS); suppressor screen; genetic double-mutant analysis; Rad52 epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus genetic epistasis with functional suppression, single lab\",\n      \"pmids\": [\"26849847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Fission yeast Mrc1 selectively binds early-firing replication origins independently of Cdc45 and Hsk1 kinase before S phase; in mrc1Δ cells, early origins (those normally Mrc1-bound) fire precociously and with higher efficiency, while late origins are unaffected. This origin-timing function requires the non-checkpoint activity of Mrc1.\",\n      \"method\": \"ChIP-on-chip (genome-wide Mrc1 binding); replication timing analysis; checkpoint-defective mrc1 allele comparison\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP with separation-of-function alleles demonstrating origin-specific regulation independent of checkpoint function\",\n      \"pmids\": [\"21518960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of MRC1 in S. cerevisiae maintains wild-type origin firing times despite >2-fold lengthening of S phase, whereas 13 other slow-S-phase mutants all showed proportional scaling of the entire replication timing program; mrc1Δ also activates numerous dormant origins.\",\n      \"method\": \"Genome-wide replication timing analysis by DNA microarray; genetic screen of 14 S-phase mutants\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide analysis distinguishing MRC1's unique role, single lab comparative screen\",\n      \"pmids\": [\"20219942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"S. cerevisiae Mrc1 plays a specific role in DNA replication that promotes Srs2 recruitment to PCNA independently of checkpoint signaling, thereby preventing crossover formation; mrc1Δ increases spontaneous crossover rates comparably to srs2Δ.\",\n      \"method\": \"Genetic screen for spontaneous crossover rates; epistasis analysis with srs2Δ, mrc1Δ, and pol30-RR (PCNA) mutants\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with quantitative crossover assay identifying non-checkpoint replication function, single lab\",\n      \"pmids\": [\"16724109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"S. cerevisiae Mrc1 protects uncapped telomeres (cdc13-1 and yku70Δ backgrounds) from Exo1-dependent nucleolytic degradation; protection is due to Mrc1's replicative function (not checkpoint function), as the checkpoint-defective mrc1AQ allele behaves like wild-type at telomeres.\",\n      \"method\": \"Genetic deletion analysis; mrc1AQ separation-of-function allele; single-stranded DNA accumulation assays; EXO1 epistasis\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — separation-of-function allele plus nuclease epistasis, defined molecular phenotype\",\n      \"pmids\": [\"17618841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"S. cerevisiae Mrc1's fork-stabilizing function (but not checkpoint activation function) is required to prevent DNA breakage and cell death at long CAG repeats; both functions contribute to preventing repeat length instability.\",\n      \"method\": \"Separation-of-function mrc1 alleles; DNA breakage assays; repeat instability assays; genetic analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — separation-of-function alleles with distinct phenotypic readouts for breakage vs. instability\",\n      \"pmids\": [\"30476303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human MRC1 gene encoding the macrophage mannose receptor is divided into 30 exons; the first three encode the signal sequence, N-terminal cysteine-rich domain, and fibronectin type II repeat; the final exon encodes the transmembrane anchor and cytoplasmic tail; the intervening 26 exons encode the eight carbohydrate-recognition domains.\",\n      \"method\": \"Genomic cloning and sequencing of the entire MRC1 coding region; exon-intron boundary mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic sequencing of entire gene locus, foundational structural characterization\",\n      \"pmids\": [\"1294118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of MRC1/CD206 C-type carbohydrate-recognition domain 4 (CRD4) in complex with mannose, GlcNAc, fucose, Manα1-2Man disaccharide, and Lewis-a trisaccharide reveal Ca2+-dependent binding mechanisms: mannose and GlcNAc engage equatorial 3- and 4-OH groups with the principal Ca2+; fucose can bind in multiple orientations; the Manα1-2Man disaccharide gains additional affinity through contacts with the reducing mannose residue.\",\n      \"method\": \"Glycan array screening; multiple crystal structures of CRD4-ligand complexes; isothermal titration calorimetry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures with distinct ligands plus functional glycan array data, rigorous structural and binding analysis\",\n      \"pmids\": [\"33545173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Pneumolysin (PLY) from S. pneumoniae binds directly to MRC1/CD206 on human dendritic cells and mouse alveolar macrophages, suppressing pro-inflammatory cytokine responses and TLR signaling, upregulating SOCS1, mediating pneumococcal internalization into non-lysosomal compartments, and polarizing T cells toward an immunoregulatory phenotype. MRC1-deficient mice show reduced bacterial loads in the airways.\",\n      \"method\": \"Direct binding assay (PLY-MRC1); MRC1 knockout mouse infection model; blocking antibody experiments; cytokine/signaling assays in dendritic cells and macrophages\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding plus receptor KO in vivo phenotype plus multiple cellular mechanistic readouts\",\n      \"pmids\": [\"30420782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MRC1/CD206 promotes ricin toxin binding and uptake into monocytes in vitro, and MRC1-knockout mice are significantly more susceptible to ricin-induced death in vivo, indicating MRC1 functions in scavenging/degradation of ricin rather than facilitating its toxicity.\",\n      \"method\": \"In vitro ricin binding and uptake assays; MRC1 knockout mouse challenge with ricin (2.5× and 5× LD50)\",\n      \"journal\": \"Toxins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assays plus KO mouse in vivo phenotype, single lab\",\n      \"pmids\": [\"22069759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD206/MRC1 on inflammatory dendritic epidermal cells (IDECs) mediates receptor-mediated endocytosis of mannosylated antigens (dextran-FITC uptake), whereas Langerhans cells that lack CD206 do not show this CD206-dependent endocytosis.\",\n      \"method\": \"Flow cytometry; dextran-FITC uptake assay; electron microscopy with immunogold staining; pinocytosis control (Lucifer yellow)\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-mediated endocytosis assay with specific inhibition, defined cellular localization by EM\",\n      \"pmids\": [\"11841552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cockroach allergen Bla g 2 (which bears mannose-terminated N-glycans) binds directly to CD206/MRC1 on human fibrocytes, and this interaction mediates allergen uptake and activation of NF-κB, p38, ERK, and JNK signaling pathways, leading to TNF-α and IL-6 production; all these effects are blocked by mannan or anti-CD206 antibody.\",\n      \"method\": \"MALDI-MS N-glycan profiling; solid-phase binding assay; antibody blocking; FITC-allergen uptake by fibrocytes; intracellular signaling (kinase phosphorylation) and cytokine assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay plus functional signaling readouts with specific blocking, single lab\",\n      \"pmids\": [\"23734186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Galectin-9 binds directly to CD206 on macrophages (Kd ~2.8 × 10^-7 M; confirmed by immunoprecipitation and blocked by anti-CD206), and this interaction induces CD206+ macrophages to produce more FGF2 and MCP-1 but less MDC, supporting a tumor-promoting microenvironment.\",\n      \"method\": \"Immunoprecipitation of CD206-galectin-9 complex from cell lysates; competition binding assay; fluorescence anisotropy for affinity measurement; cytokine secretion assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus fluorescence anisotropy affinity measurement and functional cytokine readout, single lab\",\n      \"pmids\": [\"29732570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sulfated galactose glycopolymers (SO4-3-Gal) targeting the cysteine-rich domain of CD206 block receptor function by forming stable intracellular CD206-glycopolymer complexes that prevent receptor recycling to the cell membrane, both in vitro and in vivo in mice.\",\n      \"method\": \"Endocytosis and receptor recycling assays; in vitro CD206 activity assays; in vivo administration in mice; intracellular complex characterization\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with defined molecular mechanism of receptor blockade, single lab\",\n      \"pmids\": [\"36472883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MRC1/CD206 CTLD4-7 is highly selective for pauci- and oligomannose N-glycans (among hundreds of glycans tested on glycan arrays); tumor cells and A549 lung cancer cells express MRC1-binding ligands carrying these glycans, identified by immunoprecipitation and glycoproteomics.\",\n      \"method\": \"Glycan microarray screening; flow cytometry; immunoprecipitation of MR-Fc from cancer cell lysates; glycoproteomic analysis (42 proteins identified)\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — glycan array and glycoproteomics with functional binding validation, single lab\",\n      \"pmids\": [\"34089345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RP-182 selectively activates CD206 on human and murine M2-like macrophages, inducing a conformational switch that triggers endocytosis, phagosome-lysosome formation, and autophagy, and reprograms M2-like tumor-associated macrophages to an M1-like antitumor phenotype.\",\n      \"method\": \"In vitro macrophage functional assays (endocytosis, phagosome formation); murine syngeneic/autochthonous tumor models; CD206high PDX models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assays demonstrating CD206-mediated signaling program, in vivo validation, single lab\",\n      \"pmids\": [\"32051227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD206/MRC1+ M2-like macrophages in adipose tissue inhibit adipocyte progenitor proliferation via TGF-β1 secretion and TGF-β signaling; ablation of CD206+ M2-like macrophages in transgenic mice increases smaller adipocyte numbers, reduces TGF-β signaling, and improves systemic insulin sensitivity.\",\n      \"method\": \"CD206-diphtheria toxin receptor transgenic mouse depletion model; adipocyte progenitor proliferation assays; TGF-β signaling pathway analysis; adipose tissue phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional CD206+ cell depletion with defined molecular pathway (TGF-β) and phenotypic readout, single lab\",\n      \"pmids\": [\"28819169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD206+ M2-like macrophages inhibit FAP-derived follistatin secretion via TGF-β1 signaling; depletion of CD206+ macrophages or deletion of macrophage-specific TGF-β1 activates FAPs to secrete follistatin, promoting myogenesis and muscle regeneration. FAP-specific follistatin deletion impairs muscle stem cell function.\",\n      \"method\": \"CD206-DTR transgenic mouse depletion; macrophage-specific TGF-β1 gene deletion; FAP isolation and follistatin secretion assays; muscle regeneration phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic depletion + tissue-specific gene deletion identifying TGF-β1 as the molecular effector, single lab\",\n      \"pmids\": [\"36411280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mesenchymal stem cells (UCMSCs) promote CD206 expression and phagocytic activity in macrophages through IL-6 in a mouse SLE model and in vitro with human SLE macrophages; IL-6 blockade abrogates the UCMSC-mediated increase in CD206 expression and phagocytosis.\",\n      \"method\": \"UCMSC-macrophage co-culture; IL-6 neutralization; flow cytometry; phagocytosis assays in vitro and in vivo\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IL-6 required for CD206 upregulation shown by blocking experiment, in vitro and in vivo confirmation, single lab\",\n      \"pmids\": [\"26209923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Colocalization of Mec1 (via Ddc2-LacI) and Mrc1-LacI at LacO arrays in S. cerevisiae is sufficient to activate Rad53 phosphorylation; this minimal replication checkpoint signal is independent of Ddc1 and Dpb11 (Mec1 activators required for DNA damage checkpoint).\",\n      \"method\": \"LacI-LacO tethering system (in vivo replication checkpoint mimic); Rad53 phosphorylation assays; genetic epistasis with ddc1Δ, dpb11, mrc1Δ\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthetic tethering system with defined genetic requirements, single lab\",\n      \"pmids\": [\"22298423\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRC1 encodes two functionally distinct proteins: (1) in yeast (canonical replication checkpoint protein), Mrc1/Claspin is a replisome-associated mediator that travels with replication forks, directly binds Mcm6 and Pol2 (DNA polymerase epsilon), stimulates CMG helicase unwinding rate, facilitates Mec1-dependent phosphorylation and Rad53 activation via a solid-state platform at stalled forks, and promotes parental histone H3-H4 transfer to the lagging strand for epigenetic inheritance—all separable from its checkpoint function; (2) in mammals, MRC1/CD206 is a transmembrane C-type lectin on macrophages/dendritic cells whose CRD4 mediates Ca2+-dependent binding to mannose, fucose, GlcNAc, and oligomannose glycans (structurally defined by crystal structures), enabling receptor-mediated endocytosis of pathogens and glycoproteins, direct binding of ligands including pneumolysin (suppressing inflammation) and galectin-9 (promoting pro-tumor cytokines), and paracrine signaling via TGF-β1 that regulates adipocyte progenitor proliferation and muscle regeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The MRC1 symbol maps to two molecularly distinct, internally coherent proteins in this corpus, and the timeline supports both pictures independently. In yeast, Mrc1 (mediator of the replication checkpoint, the Claspin ortholog) is a replisome-associated factor that travels with the replication fork and couples fork progression to checkpoint signaling [#0, #3]. It loads at early-firing origins before S phase and constrains their timing and efficiency independently of checkpoint function [#26], and as part of a heterotrimeric Csm3-Tof1-Mrc1 mediator complex it associates with moving forks, with Tof1/Csm3 required for Mrc1 fork association [#11]. Mrc1 directly engages the replicative helicase and polymerase—binding Mcm6 through its central coiled-coil [#13] and both halves of the Pol epsilon catalytic subunit Pol2 [#10]—and stimulates the CMG helicase to set normal fork elongation rate [#9, #19]. In its checkpoint role, Mec1/Rad3-Tel1-dependent phosphorylation at S/TQ clusters licenses Mrc1 to bridge Mec1 to Rad53/Cds1 as an enzyme-substrate platform, accelerating Rad53 activation ~70-fold via its conserved C-terminal domain [#3, #14, #44]; in fission yeast this requires Mrc1 binding the Cds1 FHA domain [#5, #6]. Checkpoint and replicative functions are cleanly separable by mutation: the replicative arm supports sister chromatid cohesion, suppression of inappropriate recombination, telomere protection, and parental histone H3-H4 transfer to the lagging strand for heterochromatin inheritance, all independent of Rad53 signaling [#7, #16, #29, #20]. Rad53-mediated phosphorylation of Mrc1 in turn slows fork elongation by blocking its CMG-stimulating activity, integrating checkpoint feedback into replication speed [#19]. The mammalian protein MRC1/CD206 is structurally and functionally unrelated: a transmembrane macrophage/dendritic-cell C-type lectin organized into a cysteine-rich domain, fibronectin type II repeat, and eight carbohydrate-recognition domains [#31], whose CRD4 mediates Ca2+-dependent recognition of mannose, GlcNAc, fucose, and oligomannose glycans as defined by crystal structures [#32, #39]. It functions as an endocytic receptor for mannosylated antigens and pathogen ligands [#35], binding pneumolysin to suppress inflammation [#33] and galectin-9 to drive a pro-tumor cytokine program [#37], and CD206+ M2-like macrophages signal through TGF-\\u03b21 to regulate adipocyte progenitor proliferation and muscle regeneration [#41, #42].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that Mrc1 is a dedicated mediator of the DNA replication checkpoint, defining a Rad53/Cds1-activating function distinct from the DNA damage checkpoint.\",\n      \"evidence\": \"mrc1\\u0394 deletion with checkpoint kinase activation assays in budding yeast, and Cds1 association/S-phase-specific activation in fission yeast\",\n      \"pmids\": [\"11715016\", \"11715017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether Mrc1 acts at forks or globally\", \"Molecular mechanism of Rad53/Cds1 activation unknown at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed Mrc1 physically travels with the replisome and that its checkpoint phosphorylation is separable from its replication role, the first separation-of-function evidence.\",\n      \"evidence\": \"ChIP tracking of Mrc1 at origins/forks, co-IP with fork components during HU arrest, and SQ/TQ phosphosite mutagenesis\",\n      \"pmids\": [\"12944972\", \"12865299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct replisome binding partners not yet mapped\", \"How Mec1 phosphorylates Mrc1 at the fork undefined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified the structural basis for Mrc1-DNA engagement and for recruiting the effector kinase, linking fork-structure sensing to checkpoint signaling.\",\n      \"evidence\": \"in vitro DNA-binding assays of an N-terminal HLH domain preferring branched DNA, plus Cds1 FHA-domain interaction mapping and cohesion/recombination genetics\",\n      \"pmids\": [\"15471884\", \"15173168\", \"15282308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of branched-DNA binding not fully established\", \"Cohesion mechanism (idx 16) Medium confidence and single-lab\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined Mrc1's role in setting fork progression rate and coupling helicase unwinding to synthesis, distinguishing it from Tof1's pausing function.\",\n      \"evidence\": \"2D gel analysis of replication intermediates, genetic epistasis, and MCM helicase co-IP with supercoiling readout in fission yeast\",\n      \"pmids\": [\"16137625\", \"15755447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism of helicase coupling not biochemically reconstituted at this stage\", \"MCM interaction (idx 8) Medium confidence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstituted the mediator architecture: Mrc1 directly binds Mcm6 and Pol2 within a Csm3-Tof1-Mrc1 complex and cooperates with Mec1 to activate Rad53, providing the biochemical platform model.\",\n      \"evidence\": \"baculovirus co-expression/co-IP of purified complex, Mcm6 and Pol2 interaction mapping with fusion-rescue, and in vitro Mec1-Mrc1-Rad53 kinase reconstitution\",\n      \"pmids\": [\"19819872\", \"19620285\", \"18851837\", \"19457865\", \"19515819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the platform at forks unresolved\", \"How phosphorylation toggles Pol2N vs Pol2C binding mechanistically unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a checkpoint-independent role in controlling replication origin timing and efficiency, showing Mrc1 selectively marks and restrains early origins.\",\n      \"evidence\": \"genome-wide ChIP-on-chip of Mrc1 binding and replication timing analysis with checkpoint-defective alleles in fission and budding yeast\",\n      \"pmids\": [\"21518960\", \"20219942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which Mrc1 restrains early origin firing undefined\", \"Connection between origin binding and fork-traveling pool unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the definitive mechanism for checkpoint-replication integration: Mrc1 stimulates CMG unwinding rate, and Rad53 phosphorylation of Mrc1 abolishes this to slow elongation.\",\n      \"evidence\": \"fully reconstituted in vitro replication with purified components, helicase assays, and phosphomimetic Mrc1 mutants in vitro and in vivo\",\n      \"pmids\": [\"34387546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phospho-regulation of CMG stimulation occurs at every fork or selectively unknown\", \"Structural basis of CMG stimulation not solved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Added an epigenetic inheritance function, showing Mrc1 routes parental H3-H4 histones to the lagging strand independently of its checkpoint and speed roles.\",\n      \"evidence\": \"separation-of-function alleles, co-IP showing Mcm2/Pol-alpha facilitation, and heterochromatin inheritance assays in fission yeast\",\n      \"pmids\": [\"39094566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of strand-biased histone deposition not fully defined\", \"Conservation of this role in mammals untested in this corpus\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the domain architecture of the unrelated mammalian MRC1/CD206 mannose receptor, defining its eight carbohydrate-recognition domains and membrane topology.\",\n      \"evidence\": \"genomic cloning and exon-intron mapping of the full human MRC1 locus\",\n      \"pmids\": [\"1294118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glycan specificity of individual CRDs not defined\", \"No structural data at this stage\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the structural and glycan-recognition basis of CD206, showing CRD4 binds mannose, GlcNAc, fucose, and oligomannose via Ca2+-dependent contacts with selectivity for pauci-/oligomannose N-glycans.\",\n      \"evidence\": \"multiple CRD4-ligand crystal structures, ITC, and glycan-array/glycoproteomic profiling of tumor-cell ligands\",\n      \"pmids\": [\"33545173\", \"34089345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contributions of the other CRDs underexplored\", \"Physiological endogenous ligand repertoire incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated CD206 as an endocytic and immunomodulatory receptor for pathogen and self ligands, linking glycan recognition to inflammation control and disease.\",\n      \"evidence\": \"direct pneumolysin and galectin-9 binding, MRC1-knockout mouse infection phenotype, and cytokine/signaling readouts in macrophages and dendritic cells\",\n      \"pmids\": [\"30420782\", \"29732570\", \"23734186\", \"11841552\", \"22069759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of CD206 ligand engagement incompletely mapped\", \"Most cellular mechanism studies are single-lab Medium confidence\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established CD206+ M2-like macrophages as TGF-\\u03b21-secreting paracrine regulators of tissue homeostasis and as actionable targets for receptor manipulation.\",\n      \"evidence\": \"CD206-DTR depletion and macrophage-specific TGF-\\u03b21 deletion in mice (adipose and muscle), plus CD206-targeting glycopolymer and agonist (RP-182) functional studies\",\n      \"pmids\": [\"36411280\", \"28819169\", \"32051227\", \"36472883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-proximal signaling distinct from cell-population effects not fully resolved\", \"TGF-\\u03b21 regulation downstream of CD206 itself not mechanistically dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how the separable yeast Mrc1/Claspin functions (checkpoint platform, CMG stimulation, origin timing, histone inheritance) are coordinated at a single fork, and whether the mammalian Claspin ortholog performs these roles; the two MRC1 proteins in this corpus share no demonstrated functional relationship.\",\n      \"evidence\": \"no timeline discovery bridges the yeast replication protein and the human CD206 lectin\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No human Claspin replication data in this corpus\", \"Symbol collision means the two protein narratives must be kept distinct\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 13, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14, 19]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [33, 35]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [35, 34, 39]},\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [32]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [31, 33, 35]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [35, 38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [0, 3, 9, 19]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [1, 14, 44]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [22, 26]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [33, 37, 41]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [35, 38]}\n    ],\n    \"complexes\": [\n      \"Csm3-Tof1-Mrc1 replication mediator complex\",\n      \"replisome / replication-pausing complex\"\n    ],\n    \"partners\": [\n      \"MCM6\",\n      \"POL2\",\n      \"MEC1\",\n      \"RAD53\",\n      \"CDS1\",\n      \"TOF1\",\n      \"CSM3\",\n      \"MCM2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}