{"gene":"MMS22L","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2010,"finding":"MMS22L (C6ORF167) forms a stable heterodimeric complex with TONSL (NFKBIL2) that accumulates at regions of ssDNA associated with distressed replication forks or processed DNA breaks, and is required for efficient RAD51 foci formation and homologous recombination-mediated repair of stalled or collapsed replication forks.","method":"Co-immunoprecipitation, siRNA depletion, immunofluorescence, camptothecin sensitivity assays, HR reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic depletion with defined cellular phenotype, independently replicated across three concurrent papers in the same journal issue","pmids":["21055983","21055985","21055984"],"is_preprint":false},{"year":2010,"finding":"MMS22L-TONSL (NFKBIL2) interacts with FACT (facilitator of chromatin transcription) and MCM (minichromosome maintenance) complexes, and depletion leads to phosphorylated RPA loading onto chromatin in a CTIP-dependent manner, activating the ATR/ATRIP-CHK1 and DSB repair signaling pathways.","method":"Mass spectrometry-based interactome, Co-IP, chromatin fractionation, siRNA knockdown","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome plus Co-IP, single lab, multiple orthogonal methods","pmids":["21055985"],"is_preprint":false},{"year":2010,"finding":"Human MMS22L is degraded in a Cul4-dependent manner upon replication stress, and unlike yeast Mms22 does not stably bind Cul4; MMS22L physically interacts with NFKBIL2/TONSL, which co-purifies with histones and chromatin remodelling factors.","method":"RNAi screen, live-cell imaging, Co-IP/mass spectrometry, protein stability assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS plus functional RNAi screen, single lab, multiple orthogonal methods","pmids":["21113133"],"is_preprint":false},{"year":2016,"finding":"The TONSL ankyrin repeat domain (ARD) reads histone H4 tails unmethylated at K20 (H4K20me0), a mark specific to newly incorporated histones after DNA replication. This interaction recruits the TONSL-MMS22L complex to post-replicative chromatin, where it binds new H3-H4 histones both before and after nucleosome incorporation, remaining until late G2/M. H4K20me0 recognition is required for TONSL-MMS22L chromatin binding and accumulation at challenged replication forks.","method":"Histone peptide binding assays, Co-IP, chromatin fractionation, TONSL ARD mutagenesis, cell cycle analysis, live imaging","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays, active-site mutagenesis of TONSL ARD, multiple orthogonal methods, single rigorous study with functional validation","pmids":["27338793"],"is_preprint":false},{"year":2016,"finding":"The MMS22L-TONSL heterodimer directly interacts with RPA-coated ssDNA, and the MMS22L subunit directly binds RAD51. Recombinant MMS22L-TONSL limits RAD51 assembly on dsDNA, thereby stimulating RAD51-ssDNA nucleoprotein filament formation and RAD51-dependent strand exchange in vitro. A MMS22L mutant deficient in RAD51 interaction fails to rescue HR-mediated repair of stalled forks in vivo.","method":"In vitro RAD51 strand exchange assays, recombinant protein reconstitution, Co-IP, site-directed mutagenesis, DNA fiber assay, iPOND","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with recombinant proteins, mutagenesis, multiple orthogonal in vivo and in vitro methods, single rigorous study","pmids":["27797818"],"is_preprint":false},{"year":2018,"finding":"Histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL recruitment to ssDNA during HR; blocking chromatin assembly via ASF1 or CAF-1 knockdown, or an ASF1A mutation preventing histone binding, reduces MMS22L-TONSL recruitment to ssDNA and impairs RAD51 loading. DNA-PKcs-dependent phosphorylation of ASF1A upon DNA damage enhances chromatin assembly, further promoting MMS22L-TONSL recruitment.","method":"siRNA knockdown, Co-IP, immunofluorescence, cell cycle analysis, ASF1A phosphorylation assay, histone-binding mutants","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via multiple knockdowns, phosphorylation mapping, Co-IP, multiple orthogonal methods; independently supported by yeast chromatin-ssDNA data","pmids":["29478807"],"is_preprint":false},{"year":2022,"finding":"MMS22L-TONSL functions in sister chromatid cohesion (SCC) establishment in a pathway parallel to DSCC1-RFC; synthetic lethality between MMS22L and DSCC1 results from detrimental SCC loss. Both DSCC1-RFC and MMS22L facilitate ESCO2 recruitment to replication forks, suggesting distinct ESCO2 recruitment pathways promote SCC after either cohesin conversion or de novo cohesin loading.","method":"Genome-wide CRISPR screens, genetic epistasis (double KO), SCC assays, ESCO2 chromatin recruitment assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR epistasis screen, functional SCC assays, single lab with multiple orthogonal methods","pmids":["36622344"],"is_preprint":false},{"year":2012,"finding":"MMS22L protein is translocated to the nucleus and stabilized by binding to the C-terminal portion of NFKBIL2/TONSL; expression of the MMS22L-interacting C-terminal fragment of NFKBIL2 in cancer cells reduces nuclear MMS22L levels. Knockdown of MMS22L inhibits TNF-α-dependent activation of RelA/p65 in the NF-κB pathway and expression of anti-apoptotic molecules Bcl-XL and TRAF1.","method":"Co-IP, siRNA knockdown, nuclear fractionation, NF-κB reporter assays, Western blot","journal":"International journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single Co-IP method for interaction, limited mechanistic follow-up for NF-κB connection","pmids":["22895565"],"is_preprint":false},{"year":2025,"finding":"Replication stress stimulates formation of an interdependent complex between FANCM and the TONSL-MMS22L heterodimer on chromatin. TONSL-MMS22L recruits FANCM and the FA core complex to stalled/collapsed forks, promotes FANCD2 monoubiquitination, and facilitates repair and replication traverse of ICLs through interactions with FANCM and H3-H4. Reciprocally, FANCM DNA translocase activity and phosphorylation facilitate TONSL-MMS22L and RAD51 recruitment to perturbed forks.","method":"Co-IP, chromatin fractionation, iPOND, FANCD2 ubiquitination assay, ICL repair and fork traverse assays, phosphorylation mapping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and cell biological methods, single lab, preprint not yet peer-reviewed","pmids":["41030968"],"is_preprint":true},{"year":2024,"finding":"The MMS22L-TONSL complex interacts with the anti-recombinase FIGNL1, and is critical for homologous recombination in BRCA2/FIGNL1 double-deficient cells.","method":"Co-IP, genetic epistasis (double KO mouse embryonic stem cells), HR assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for interaction, preprint, limited mechanistic follow-up specific to MMS22L","pmids":["bio_10.1101_2024.11.03.621741"],"is_preprint":true},{"year":2025,"finding":"Loss of MMS22L in human erythroid progenitors causes proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations. MMS22L and CDAN1 are components of the same protein complex whose nuclear import is mediated by importin 4 (IPO4); nuclear import of MMS22L is impaired in CDAI patients due to a defective CDAN1-IPO4 interaction.","method":"siRNA knockdown in human erythroid progenitors, zebrafish haploinsufficiency model, Co-IP, nuclear fractionation, p53 pathway activation assays","journal":"HemaSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, genetic model (zebrafish), functional differentiation assays, single lab with multiple orthogonal methods","pmids":["41446536"],"is_preprint":false}],"current_model":"MMS22L forms a stable heterodimer with TONSL that is recruited to post-replicative chromatin via the TONSL ankyrin repeat domain reading H4K20me0 on newly incorporated histones; at stalled or collapsed replication forks, MMS22L directly binds RAD51 and, together with TONSL, limits RAD51 assembly on dsDNA to stimulate productive RAD51-ssDNA nucleofilament formation and strand exchange, a process further facilitated by histone chaperones ASF1/CAF-1; the complex also recruits FANCM and the FA core complex to perturbed forks to promote ICL repair, participates in sister chromatid cohesion establishment via ESCO2 recruitment in parallel to DSCC1-RFC, and in erythroid cells partners with CDAN1 in a complex whose nuclear import is IPO4-dependent."},"narrative":{"mechanistic_narrative":"MMS22L is a genome-maintenance factor that operates as a stable heterodimer with TONSL to promote homologous recombination-mediated repair of stalled and collapsed replication forks [PMID:21055983, PMID:21055985, PMID:21055984]. The complex is targeted to newly replicated chromatin by the TONSL ankyrin repeat domain, which reads histone H4 unmethylated at K20 (H4K20me0) on freshly deposited histones, an interaction required for accumulation at challenged forks and retained on chromatin until late G2/M [PMID:27338793]. At sites of replication stress the heterodimer engages RPA-coated ssDNA, and the MMS22L subunit directly binds RAD51; reconstituted MMS22L-TONSL limits RAD51 assembly on dsDNA and thereby stimulates productive RAD51-ssDNA nucleofilament formation and strand exchange, an activity essential for fork repair in vivo [PMID:27797818]. Recruitment of the complex to ssDNA is coupled to ongoing chromatin assembly through the histone chaperones ASF1 and CAF-1, with DNA-PKcs-dependent ASF1A phosphorylation enhancing this loading [PMID:29478807]. Beyond RAD51 control, MMS22L-TONSL recruits FANCM and the FA core complex to perturbed forks to drive FANCD2 monoubiquitination and interstrand crosslink traverse [PMID:41030968], and contributes to sister chromatid cohesion establishment by facilitating ESCO2 recruitment in a pathway parallel to DSCC1-RFC [PMID:36622344]. In erythroid progenitors MMS22L forms a complex with CDAN1 whose nuclear import depends on importin 4 (IPO4), and its loss arrests proliferation and differentiation with p53 activation [PMID:41446536].","teleology":[{"year":2010,"claim":"Established MMS22L as a TONSL-binding factor required for RAD51 focus formation and HR repair of damaged forks, defining its core genome-maintenance role.","evidence":"Reciprocal Co-IP, siRNA depletion, HR reporter and camptothecin sensitivity assays across three concurrent papers","pmids":["21055983","21055985","21055984"],"confidence":"High","gaps":["Molecular mechanism by which the complex promotes RAD51 loading not yet defined","How the complex is recruited to chromatin unresolved"]},{"year":2010,"claim":"Linked MMS22L-TONSL loss to ssDNA/RPA accumulation and ATR-CHK1 checkpoint activation, placing it upstream of replication stress signaling.","evidence":"MS interactome, Co-IP, chromatin fractionation and siRNA knockdown identifying FACT and MCM associations","pmids":["21055985"],"confidence":"Medium","gaps":["Functional significance of FACT/MCM interactions not dissected","Whether checkpoint activation is a direct or indirect consequence unclear"]},{"year":2010,"claim":"Showed human MMS22L is degraded Cul4-dependently upon replication stress, distinguishing its regulation from yeast Mms22.","evidence":"RNAi screen, live-cell imaging, Co-IP/MS and protein stability assays","pmids":["21113133"],"confidence":"Medium","gaps":["Cul4 substrate adaptor and degradation signal not identified","Functional purpose of stress-induced degradation unclear"]},{"year":2012,"claim":"Reported that TONSL C-terminus stabilizes and nuclear-localizes MMS22L and connected MMS22L to TNF-alpha/NF-kappaB signaling.","evidence":"Co-IP, nuclear fractionation, NF-kappaB reporter assays and Western blot in cancer cells","pmids":["22895565"],"confidence":"Low","gaps":["NF-kappaB connection rests on single-lab Co-IP with limited mechanistic follow-up","Direct versus indirect role in RelA activation not established"]},{"year":2016,"claim":"Defined the chromatin-targeting mechanism: the TONSL ankyrin repeat domain reads H4K20me0 on new histones to recruit the complex to post-replicative chromatin.","evidence":"Histone peptide binding assays, TONSL ARD mutagenesis, chromatin fractionation, cell cycle analysis and live imaging","pmids":["27338793"],"confidence":"High","gaps":["How H4K20me0 reading is coupled to fork repair activity not fully resolved","Timing of complex eviction in G2/M mechanistically undefined"]},{"year":2016,"claim":"Provided the biochemical mechanism: MMS22L directly binds RAD51 and the heterodimer limits RAD51-dsDNA binding to favor RAD51-ssDNA filament formation and strand exchange.","evidence":"Reconstituted in vitro strand exchange with recombinant proteins, RAD51-interaction mutants, DNA fiber assay and iPOND","pmids":["27797818"],"confidence":"High","gaps":["Structural basis of RAD51 selectivity for ssDNA over dsDNA not determined","Stoichiometry of the MMS22L-TONSL-RAD51 assembly unknown"]},{"year":2018,"claim":"Connected complex recruitment to ongoing chromatin assembly, showing ASF1/CAF-1 and DNA-PKcs-phosphorylated ASF1A promote MMS22L-TONSL loading at ssDNA.","evidence":"siRNA knockdowns, histone-binding mutants, ASF1A phosphorylation assay, Co-IP and immunofluorescence","pmids":["29478807"],"confidence":"High","gaps":["Order of histone deposition versus complex recruitment not fully defined","Whether new-histone deposition is obligatory for all complex functions unknown"]},{"year":2022,"claim":"Extended MMS22L function beyond repair to sister chromatid cohesion via ESCO2 recruitment, explaining synthetic lethality with DSCC1.","evidence":"Genome-wide CRISPR screens, double-knockout epistasis, SCC and ESCO2 chromatin recruitment assays","pmids":["36622344"],"confidence":"Medium","gaps":["Mechanism of ESCO2 recruitment by MMS22L not biochemically defined","Relationship between cohesion and HR functions of the complex unclear"]},{"year":2024,"claim":"Identified an interaction with the anti-recombinase FIGNL1, positioning MMS22L-TONSL as critical for HR in BRCA2/FIGNL1 double-deficient cells.","evidence":"Co-IP and double-knockout HR assays in mouse embryonic stem cells (preprint)","pmids":["bio_10.1101_2024.11.03.621741"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation specific to MMS22L","Functional consequence of the FIGNL1 interaction not mechanistically dissected"]},{"year":2025,"claim":"Showed MMS22L-TONSL coordinates with FANCM and the FA core complex to drive FANCD2 monoubiquitination and ICL traverse, integrating the complex into crosslink repair.","evidence":"Co-IP, iPOND, FANCD2 ubiquitination assay, ICL repair/fork traverse assays and phosphorylation mapping (preprint)","pmids":["41030968"],"confidence":"Medium","gaps":["Awaits peer review","Direct interaction interface between TONSL-MMS22L and FANCM not mapped"]},{"year":2025,"claim":"Revealed a tissue-specific role: MMS22L forms an IPO4-imported complex with CDAN1 whose disruption underlies an erythroid differentiation defect with p53 activation.","evidence":"siRNA knockdown in human erythroid progenitors, zebrafish haploinsufficiency model, Co-IP and nuclear fractionation","pmids":["41446536"],"confidence":"Medium","gaps":["Whether the CDAN1 complex is functionally distinct from the TONSL complex unclear","Mechanism linking MMS22L loss to p53 activation not defined"]},{"year":null,"claim":"How the multiple roles of MMS22L-TONSL — RAD51 control, ICL repair, cohesion, and erythroid CDAN1 partnership — are coordinated or partitioned remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the MMS22L-TONSL heterodimer or its substrate complexes","Unclear whether distinct complexes or one complex execute the different functions","Switching between cohesion, HR, and ICL functions not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3]}],"complexes":["MMS22L-TONSL heterodimer","MMS22L-CDAN1 complex"],"partners":["TONSL","RAD51","ASF1A","CAF-1","FANCM","ESCO2","CDAN1","FIGNL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZRQ5","full_name":"Protein MMS22-like","aliases":["Methyl methanesulfonate-sensitivity protein 22-like"],"length_aa":1243,"mass_kda":142.3,"function":"Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:21113133, PubMed:26527279, PubMed:27338793, PubMed:29478807). The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:27797818). It mediates the assembly of RAD51 filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is recruited to DSBs following histone replacement by histone chaperones and eviction of the replication protein A complex (RPA/RP-A) from DSBs (PubMed:21055983, PubMed:21055984, PubMed:21055985, PubMed:29478807). Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination (PubMed:27797818, PubMed:29478807). Within the complex, MMS22L acts by binding ssDNA (PubMed:27797818)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q6ZRQ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MMS22L","classification":"Common Essential","n_dependent_lines":1198,"n_total_lines":1208,"dependency_fraction":0.9917218543046358},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"SUPT16H","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MMS22L","total_profiled":1310},"omim":[{"mim_id":"615614","title":"MMS22-LIKE PROTEIN; MMS22L","url":"https://www.omim.org/entry/615614"},{"mim_id":"615383","title":"FIDGETIN-LIKE PROTEIN 1; FIGNL1","url":"https://www.omim.org/entry/615383"},{"mim_id":"604546","title":"TONSOKU-LIKE DNA REPAIR PROTEIN; TONSL","url":"https://www.omim.org/entry/604546"},{"mim_id":"602822","title":"H4 CLUSTERED HISTONE 1; H4C1","url":"https://www.omim.org/entry/602822"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":6.7},{"tissue":"testis","ntpm":6.4}],"url":"https://www.proteinatlas.org/search/MMS22L"},"hgnc":{"alias_symbol":["dJ39B17.2"],"prev_symbol":["C6orf167"]},"alphafold":{"accession":"Q6ZRQ5","domains":[{"cath_id":"-","chopping":"257-333_340-380","consensus_level":"high","plddt":81.1727,"start":257,"end":380},{"cath_id":"-","chopping":"418-585","consensus_level":"medium","plddt":83.6267,"start":418,"end":585},{"cath_id":"-","chopping":"588-729","consensus_level":"medium","plddt":86.5796,"start":588,"end":729},{"cath_id":"-","chopping":"1166-1243","consensus_level":"medium","plddt":83.8627,"start":1166,"end":1243},{"cath_id":"1.10.357","chopping":"53-239","consensus_level":"high","plddt":81.9541,"start":53,"end":239},{"cath_id":"1.20.1050","chopping":"1036-1147","consensus_level":"medium","plddt":81.5875,"start":1036,"end":1147}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZRQ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZRQ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZRQ5-F1-predicted_aligned_error_v6.png","plddt_mean":81.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMS22L","jax_strain_url":"https://www.jax.org/strain/search?query=MMS22L"},"sequence":{"accession":"Q6ZRQ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZRQ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZRQ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZRQ5"}},"corpus_meta":[{"pmid":"27338793","id":"PMC_27338793","title":"H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex.","date":"2016","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/27338793","citation_count":178,"is_preprint":false},{"pmid":"21055983","id":"PMC_21055983","title":"The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21055983","citation_count":122,"is_preprint":false},{"pmid":"21055985","id":"PMC_21055985","title":"A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21055985","citation_count":107,"is_preprint":false},{"pmid":"21055984","id":"PMC_21055984","title":"Identification of the MMS22L-TONSL complex that promotes homologous recombination.","date":"2010","source":"Molecular 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Recurrent Frameshift Ashkenazi Jewish Founder Mutation (F722fs) in the PARP Inhibitor-sensitive MMS22L Gene Associated with Higher Risk of Prostate Cancer.","date":"2025","source":"European urology focus","url":"https://pubmed.ncbi.nlm.nih.gov/40189997","citation_count":4,"is_preprint":false},{"pmid":"34660277","id":"PMC_34660277","title":"MMS22L Expression as a Predictive Biomarker for the Efficacy of Neoadjuvant Chemoradiotherapy in Oesophageal Squamous Cell Carcinoma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34660277","citation_count":4,"is_preprint":false},{"pmid":"36276962","id":"PMC_36276962","title":"Integrative pan-cancer landscape of MMS22L and its potential role in hepatocellular carcinoma.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36276962","citation_count":3,"is_preprint":false},{"pmid":"41446536","id":"PMC_41446536","title":"MMS22L is a novel key actor of normal and pathological erythropoiesis.","date":"2025","source":"HemaSphere","url":"https://pubmed.ncbi.nlm.nih.gov/41446536","citation_count":1,"is_preprint":false},{"pmid":"41030968","id":"PMC_41030968","title":"The TONSL-MMS22L complex and FANCM form an interdependent complex on chromatin to counter replication stress.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41030968","citation_count":0,"is_preprint":false},{"pmid":"41570124","id":"PMC_41570124","title":"Treatment Response and Outcomes of Prostate Cancer Patients Carrying the Germline MMS22L F722fs Mutation.","date":"2026","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/41570124","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.03.621741","title":"FIGNL1 inhibits homologous recombination in BRCA2 deficient cells by dissociating RAD51 filaments","date":"2024-11-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.03.621741","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10462,"output_tokens":3007,"usd":0.038246,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10387,"output_tokens":3849,"usd":0.07408,"stage2_stop_reason":"end_turn"},"total_usd":0.112326,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"MMS22L (C6ORF167) forms a stable heterodimeric complex with TONSL (NFKBIL2) that accumulates at regions of ssDNA associated with distressed replication forks or processed DNA breaks, and is required for efficient RAD51 foci formation and homologous recombination-mediated repair of stalled or collapsed replication forks.\",\n      \"method\": \"Co-immunoprecipitation, siRNA depletion, immunofluorescence, camptothecin sensitivity assays, HR reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic depletion with defined cellular phenotype, independently replicated across three concurrent papers in the same journal issue\",\n      \"pmids\": [\"21055983\", \"21055985\", \"21055984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MMS22L-TONSL (NFKBIL2) interacts with FACT (facilitator of chromatin transcription) and MCM (minichromosome maintenance) complexes, and depletion leads to phosphorylated RPA loading onto chromatin in a CTIP-dependent manner, activating the ATR/ATRIP-CHK1 and DSB repair signaling pathways.\",\n      \"method\": \"Mass spectrometry-based interactome, Co-IP, chromatin fractionation, siRNA knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome plus Co-IP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21055985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Human MMS22L is degraded in a Cul4-dependent manner upon replication stress, and unlike yeast Mms22 does not stably bind Cul4; MMS22L physically interacts with NFKBIL2/TONSL, which co-purifies with histones and chromatin remodelling factors.\",\n      \"method\": \"RNAi screen, live-cell imaging, Co-IP/mass spectrometry, protein stability assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS plus functional RNAi screen, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21113133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The TONSL ankyrin repeat domain (ARD) reads histone H4 tails unmethylated at K20 (H4K20me0), a mark specific to newly incorporated histones after DNA replication. This interaction recruits the TONSL-MMS22L complex to post-replicative chromatin, where it binds new H3-H4 histones both before and after nucleosome incorporation, remaining until late G2/M. H4K20me0 recognition is required for TONSL-MMS22L chromatin binding and accumulation at challenged replication forks.\",\n      \"method\": \"Histone peptide binding assays, Co-IP, chromatin fractionation, TONSL ARD mutagenesis, cell cycle analysis, live imaging\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays, active-site mutagenesis of TONSL ARD, multiple orthogonal methods, single rigorous study with functional validation\",\n      \"pmids\": [\"27338793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The MMS22L-TONSL heterodimer directly interacts with RPA-coated ssDNA, and the MMS22L subunit directly binds RAD51. Recombinant MMS22L-TONSL limits RAD51 assembly on dsDNA, thereby stimulating RAD51-ssDNA nucleoprotein filament formation and RAD51-dependent strand exchange in vitro. A MMS22L mutant deficient in RAD51 interaction fails to rescue HR-mediated repair of stalled forks in vivo.\",\n      \"method\": \"In vitro RAD51 strand exchange assays, recombinant protein reconstitution, Co-IP, site-directed mutagenesis, DNA fiber assay, iPOND\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with recombinant proteins, mutagenesis, multiple orthogonal in vivo and in vitro methods, single rigorous study\",\n      \"pmids\": [\"27797818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Histone chaperones ASF1 and CAF-1 promote MMS22L-TONSL recruitment to ssDNA during HR; blocking chromatin assembly via ASF1 or CAF-1 knockdown, or an ASF1A mutation preventing histone binding, reduces MMS22L-TONSL recruitment to ssDNA and impairs RAD51 loading. DNA-PKcs-dependent phosphorylation of ASF1A upon DNA damage enhances chromatin assembly, further promoting MMS22L-TONSL recruitment.\",\n      \"method\": \"siRNA knockdown, Co-IP, immunofluorescence, cell cycle analysis, ASF1A phosphorylation assay, histone-binding mutants\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via multiple knockdowns, phosphorylation mapping, Co-IP, multiple orthogonal methods; independently supported by yeast chromatin-ssDNA data\",\n      \"pmids\": [\"29478807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MMS22L-TONSL functions in sister chromatid cohesion (SCC) establishment in a pathway parallel to DSCC1-RFC; synthetic lethality between MMS22L and DSCC1 results from detrimental SCC loss. Both DSCC1-RFC and MMS22L facilitate ESCO2 recruitment to replication forks, suggesting distinct ESCO2 recruitment pathways promote SCC after either cohesin conversion or de novo cohesin loading.\",\n      \"method\": \"Genome-wide CRISPR screens, genetic epistasis (double KO), SCC assays, ESCO2 chromatin recruitment assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR epistasis screen, functional SCC assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36622344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MMS22L protein is translocated to the nucleus and stabilized by binding to the C-terminal portion of NFKBIL2/TONSL; expression of the MMS22L-interacting C-terminal fragment of NFKBIL2 in cancer cells reduces nuclear MMS22L levels. Knockdown of MMS22L inhibits TNF-α-dependent activation of RelA/p65 in the NF-κB pathway and expression of anti-apoptotic molecules Bcl-XL and TRAF1.\",\n      \"method\": \"Co-IP, siRNA knockdown, nuclear fractionation, NF-κB reporter assays, Western blot\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single Co-IP method for interaction, limited mechanistic follow-up for NF-κB connection\",\n      \"pmids\": [\"22895565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Replication stress stimulates formation of an interdependent complex between FANCM and the TONSL-MMS22L heterodimer on chromatin. TONSL-MMS22L recruits FANCM and the FA core complex to stalled/collapsed forks, promotes FANCD2 monoubiquitination, and facilitates repair and replication traverse of ICLs through interactions with FANCM and H3-H4. Reciprocally, FANCM DNA translocase activity and phosphorylation facilitate TONSL-MMS22L and RAD51 recruitment to perturbed forks.\",\n      \"method\": \"Co-IP, chromatin fractionation, iPOND, FANCD2 ubiquitination assay, ICL repair and fork traverse assays, phosphorylation mapping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and cell biological methods, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41030968\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The MMS22L-TONSL complex interacts with the anti-recombinase FIGNL1, and is critical for homologous recombination in BRCA2/FIGNL1 double-deficient cells.\",\n      \"method\": \"Co-IP, genetic epistasis (double KO mouse embryonic stem cells), HR assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for interaction, preprint, limited mechanistic follow-up specific to MMS22L\",\n      \"pmids\": [\"bio_10.1101_2024.11.03.621741\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of MMS22L in human erythroid progenitors causes proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations. MMS22L and CDAN1 are components of the same protein complex whose nuclear import is mediated by importin 4 (IPO4); nuclear import of MMS22L is impaired in CDAI patients due to a defective CDAN1-IPO4 interaction.\",\n      \"method\": \"siRNA knockdown in human erythroid progenitors, zebrafish haploinsufficiency model, Co-IP, nuclear fractionation, p53 pathway activation assays\",\n      \"journal\": \"HemaSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, genetic model (zebrafish), functional differentiation assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41446536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMS22L forms a stable heterodimer with TONSL that is recruited to post-replicative chromatin via the TONSL ankyrin repeat domain reading H4K20me0 on newly incorporated histones; at stalled or collapsed replication forks, MMS22L directly binds RAD51 and, together with TONSL, limits RAD51 assembly on dsDNA to stimulate productive RAD51-ssDNA nucleofilament formation and strand exchange, a process further facilitated by histone chaperones ASF1/CAF-1; the complex also recruits FANCM and the FA core complex to perturbed forks to promote ICL repair, participates in sister chromatid cohesion establishment via ESCO2 recruitment in parallel to DSCC1-RFC, and in erythroid cells partners with CDAN1 in a complex whose nuclear import is IPO4-dependent.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMS22L is a genome-maintenance factor that operates as a stable heterodimer with TONSL to promote homologous recombination-mediated repair of stalled and collapsed replication forks [#0]. The complex is targeted to newly replicated chromatin by the TONSL ankyrin repeat domain, which reads histone H4 unmethylated at K20 (H4K20me0) on freshly deposited histones, an interaction required for accumulation at challenged forks and retained on chromatin until late G2/M [#3]. At sites of replication stress the heterodimer engages RPA-coated ssDNA, and the MMS22L subunit directly binds RAD51; reconstituted MMS22L-TONSL limits RAD51 assembly on dsDNA and thereby stimulates productive RAD51-ssDNA nucleofilament formation and strand exchange, an activity essential for fork repair in vivo [#4]. Recruitment of the complex to ssDNA is coupled to ongoing chromatin assembly through the histone chaperones ASF1 and CAF-1, with DNA-PKcs-dependent ASF1A phosphorylation enhancing this loading [#5]. Beyond RAD51 control, MMS22L-TONSL recruits FANCM and the FA core complex to perturbed forks to drive FANCD2 monoubiquitination and interstrand crosslink traverse [#8], and contributes to sister chromatid cohesion establishment by facilitating ESCO2 recruitment in a pathway parallel to DSCC1-RFC [#6]. In erythroid progenitors MMS22L forms a complex with CDAN1 whose nuclear import depends on importin 4 (IPO4), and its loss arrests proliferation and differentiation with p53 activation [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established MMS22L as a TONSL-binding factor required for RAD51 focus formation and HR repair of damaged forks, defining its core genome-maintenance role.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, HR reporter and camptothecin sensitivity assays across three concurrent papers\",\n      \"pmids\": [\"21055983\", \"21055985\", \"21055984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which the complex promotes RAD51 loading not yet defined\", \"How the complex is recruited to chromatin unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked MMS22L-TONSL loss to ssDNA/RPA accumulation and ATR-CHK1 checkpoint activation, placing it upstream of replication stress signaling.\",\n      \"evidence\": \"MS interactome, Co-IP, chromatin fractionation and siRNA knockdown identifying FACT and MCM associations\",\n      \"pmids\": [\"21055985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of FACT/MCM interactions not dissected\", \"Whether checkpoint activation is a direct or indirect consequence unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed human MMS22L is degraded Cul4-dependently upon replication stress, distinguishing its regulation from yeast Mms22.\",\n      \"evidence\": \"RNAi screen, live-cell imaging, Co-IP/MS and protein stability assays\",\n      \"pmids\": [\"21113133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cul4 substrate adaptor and degradation signal not identified\", \"Functional purpose of stress-induced degradation unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reported that TONSL C-terminus stabilizes and nuclear-localizes MMS22L and connected MMS22L to TNF-alpha/NF-kappaB signaling.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, NF-kappaB reporter assays and Western blot in cancer cells\",\n      \"pmids\": [\"22895565\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NF-kappaB connection rests on single-lab Co-IP with limited mechanistic follow-up\", \"Direct versus indirect role in RelA activation not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the chromatin-targeting mechanism: the TONSL ankyrin repeat domain reads H4K20me0 on new histones to recruit the complex to post-replicative chromatin.\",\n      \"evidence\": \"Histone peptide binding assays, TONSL ARD mutagenesis, chromatin fractionation, cell cycle analysis and live imaging\",\n      \"pmids\": [\"27338793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How H4K20me0 reading is coupled to fork repair activity not fully resolved\", \"Timing of complex eviction in G2/M mechanistically undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the biochemical mechanism: MMS22L directly binds RAD51 and the heterodimer limits RAD51-dsDNA binding to favor RAD51-ssDNA filament formation and strand exchange.\",\n      \"evidence\": \"Reconstituted in vitro strand exchange with recombinant proteins, RAD51-interaction mutants, DNA fiber assay and iPOND\",\n      \"pmids\": [\"27797818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RAD51 selectivity for ssDNA over dsDNA not determined\", \"Stoichiometry of the MMS22L-TONSL-RAD51 assembly unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected complex recruitment to ongoing chromatin assembly, showing ASF1/CAF-1 and DNA-PKcs-phosphorylated ASF1A promote MMS22L-TONSL loading at ssDNA.\",\n      \"evidence\": \"siRNA knockdowns, histone-binding mutants, ASF1A phosphorylation assay, Co-IP and immunofluorescence\",\n      \"pmids\": [\"29478807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of histone deposition versus complex recruitment not fully defined\", \"Whether new-histone deposition is obligatory for all complex functions unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended MMS22L function beyond repair to sister chromatid cohesion via ESCO2 recruitment, explaining synthetic lethality with DSCC1.\",\n      \"evidence\": \"Genome-wide CRISPR screens, double-knockout epistasis, SCC and ESCO2 chromatin recruitment assays\",\n      \"pmids\": [\"36622344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ESCO2 recruitment by MMS22L not biochemically defined\", \"Relationship between cohesion and HR functions of the complex unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an interaction with the anti-recombinase FIGNL1, positioning MMS22L-TONSL as critical for HR in BRCA2/FIGNL1 double-deficient cells.\",\n      \"evidence\": \"Co-IP and double-knockout HR assays in mouse embryonic stem cells (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.11.03.621741\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation specific to MMS22L\", \"Functional consequence of the FIGNL1 interaction not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed MMS22L-TONSL coordinates with FANCM and the FA core complex to drive FANCD2 monoubiquitination and ICL traverse, integrating the complex into crosslink repair.\",\n      \"evidence\": \"Co-IP, iPOND, FANCD2 ubiquitination assay, ICL repair/fork traverse assays and phosphorylation mapping (preprint)\",\n      \"pmids\": [\"41030968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Awaits peer review\", \"Direct interaction interface between TONSL-MMS22L and FANCM not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a tissue-specific role: MMS22L forms an IPO4-imported complex with CDAN1 whose disruption underlies an erythroid differentiation defect with p53 activation.\",\n      \"evidence\": \"siRNA knockdown in human erythroid progenitors, zebrafish haploinsufficiency model, Co-IP and nuclear fractionation\",\n      \"pmids\": [\"41446536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the CDAN1 complex is functionally distinct from the TONSL complex unclear\", \"Mechanism linking MMS22L loss to p53 activation not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple roles of MMS22L-TONSL — RAD51 control, ICL repair, cohesion, and erythroid CDAN1 partnership — are coordinated or partitioned remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the MMS22L-TONSL heterodimer or its substrate complexes\", \"Unclear whether distinct complexes or one complex execute the different functions\", \"Switching between cohesion, HR, and ICL functions not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"MMS22L-TONSL heterodimer\",\n      \"MMS22L-CDAN1 complex\"\n    ],\n    \"partners\": [\n      \"TONSL\",\n      \"RAD51\",\n      \"ASF1A\",\n      \"CAF-1\",\n      \"FANCM\",\n      \"ESCO2\",\n      \"CDAN1\",\n      \"FIGNL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}