Affinage

MMS22L

Protein MMS22-like · UniProt Q6ZRQ5

Length
1243 aa
Mass
142.3 kDa
Annotated
2026-06-10
16 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    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

    PMID:21055983 PMID:21055984 PMID:21055985

    Open questions at the time
    • Molecular mechanism by which the complex promotes RAD51 loading not yet defined
    • How the complex is recruited to chromatin unresolved
  2. 2010 Medium

    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

    PMID:21055985

    Open questions at the time
    • Functional significance of FACT/MCM interactions not dissected
    • Whether checkpoint activation is a direct or indirect consequence unclear
  3. 2010 Medium

    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

    PMID:21113133

    Open questions at the time
    • Cul4 substrate adaptor and degradation signal not identified
    • Functional purpose of stress-induced degradation unclear
  4. 2012 Low

    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

    PMID:22895565

    Open questions at the time
    • NF-kappaB connection rests on single-lab Co-IP with limited mechanistic follow-up
    • Direct versus indirect role in RelA activation not established
  5. 2016 High

    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

    PMID:27338793

    Open questions at the time
    • How H4K20me0 reading is coupled to fork repair activity not fully resolved
    • Timing of complex eviction in G2/M mechanistically undefined
  6. 2016 High

    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

    PMID:27797818

    Open questions at the time
    • Structural basis of RAD51 selectivity for ssDNA over dsDNA not determined
    • Stoichiometry of the MMS22L-TONSL-RAD51 assembly unknown
  7. 2018 High

    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

    PMID:29478807

    Open questions at the time
    • Order of histone deposition versus complex recruitment not fully defined
    • Whether new-histone deposition is obligatory for all complex functions unknown
  8. 2022 Medium

    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

    PMID:36622344

    Open questions at the time
    • Mechanism of ESCO2 recruitment by MMS22L not biochemically defined
    • Relationship between cohesion and HR functions of the complex unclear
  9. 2024 Low

    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)

    PMID:bio_10.1101_2024.11.03.621741

    Open questions at the time
    • Single Co-IP without reciprocal validation specific to MMS22L
    • Functional consequence of the FIGNL1 interaction not mechanistically dissected
  10. 2025 Medium

    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)

    PMID:41030968

    Open questions at the time
    • Awaits peer review
    • Direct interaction interface between TONSL-MMS22L and FANCM not mapped
  11. 2025 Medium

    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

    PMID:41446536

    Open questions at the time
    • Whether the CDAN1 complex is functionally distinct from the TONSL complex unclear
    • Mechanism linking MMS22L loss to p53 activation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple roles of MMS22L-TONSL — RAD51 control, ICL repair, cohesion, and erythroid CDAN1 partnership — are coordinated or partitioned remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0003677 DNA binding 1 GO:0042393 histone binding 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-69306 DNA Replication 2 R-HSA-73894 DNA Repair 2 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1
Partners
ASF1ACAF-1CDAN1ESCO2FANCMFIGNL1RAD51TONSL
Complex memberships
MMS22L-CDAN1 complexMMS22L-TONSL heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. Co-immunoprecipitation, siRNA depletion, immunofluorescence, camptothecin sensitivity assays, HR reporter assays Molecular cell High 21055983 21055984 21055985
2010 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. Mass spectrometry-based interactome, Co-IP, chromatin fractionation, siRNA knockdown Molecular cell Medium 21055985
2010 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. RNAi screen, live-cell imaging, Co-IP/mass spectrometry, protein stability assays The EMBO journal Medium 21113133
2016 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. Histone peptide binding assays, Co-IP, chromatin fractionation, TONSL ARD mutagenesis, cell cycle analysis, live imaging Nature High 27338793
2016 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. In vitro RAD51 strand exchange assays, recombinant protein reconstitution, Co-IP, site-directed mutagenesis, DNA fiber assay, iPOND The EMBO journal High 27797818
2018 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. siRNA knockdown, Co-IP, immunofluorescence, cell cycle analysis, ASF1A phosphorylation assay, histone-binding mutants Molecular cell High 29478807
2022 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. Genome-wide CRISPR screens, genetic epistasis (double KO), SCC assays, ESCO2 chromatin recruitment assays Life science alliance Medium 36622344
2012 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. Co-IP, siRNA knockdown, nuclear fractionation, NF-κB reporter assays, Western blot International journal of oncology Low 22895565
2025 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. Co-IP, chromatin fractionation, iPOND, FANCD2 ubiquitination assay, ICL repair and fork traverse assays, phosphorylation mapping bioRxivpreprint Medium 41030968
2024 The MMS22L-TONSL complex interacts with the anti-recombinase FIGNL1, and is critical for homologous recombination in BRCA2/FIGNL1 double-deficient cells. Co-IP, genetic epistasis (double KO mouse embryonic stem cells), HR assays bioRxivpreprint Low bio_10.1101_2024.11.03.621741
2025 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. siRNA knockdown in human erythroid progenitors, zebrafish haploinsufficiency model, Co-IP, nuclear fractionation, p53 pathway activation assays HemaSphere Medium 41446536

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 H4K20me0 marks post-replicative chromatin and recruits the TONSL–MMS22L DNA repair complex. Nature 178 27338793
2010 The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination. Molecular cell 122 21055983
2010 A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Molecular cell 107 21055985
2010 Identification of the MMS22L-TONSL complex that promotes homologous recombination. Molecular cell 104 21055984
2018 The Histone Chaperones ASF1 and CAF-1 Promote MMS22L-TONSL-Mediated Rad51 Loading onto ssDNA during Homologous Recombination in Human Cells. Molecular cell 81 29478807
2016 The MMS22L-TONSL heterodimer directly promotes RAD51-dependent recombination upon replication stress. The EMBO journal 75 27797818
2010 RNAi-based screening identifies the Mms22L-Nfkbil2 complex as a novel regulator of DNA replication in human cells. The EMBO journal 69 21113133
2012 Identification of a novel oncogene, MMS22L, involved in lung and esophageal carcinogenesis. International journal of oncology 21 22895565
2022 MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC. Life science alliance 14 36622344
2021 The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer. Frontiers in molecular biosciences 11 34124145
2025 Discovery of a Recurrent Frameshift Ashkenazi Jewish Founder Mutation (F722fs) in the PARP Inhibitor-sensitive MMS22L Gene Associated with Higher Risk of Prostate Cancer. European urology focus 4 40189997
2021 MMS22L Expression as a Predictive Biomarker for the Efficacy of Neoadjuvant Chemoradiotherapy in Oesophageal Squamous Cell Carcinoma. Frontiers in oncology 4 34660277
2022 Integrative pan-cancer landscape of MMS22L and its potential role in hepatocellular carcinoma. Frontiers in genetics 3 36276962
2025 MMS22L is a novel key actor of normal and pathological erythropoiesis. HemaSphere 1 41446536
2026 Treatment Response and Outcomes of Prostate Cancer Patients Carrying the Germline MMS22L F722fs Mutation. The Prostate 0 41570124
2025 The TONSL-MMS22L complex and FANCM form an interdependent complex on chromatin to counter replication stress. bioRxiv : the preprint server for biology 0 41030968

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