Affinage

MMS22L

Protein MMS22-like · UniProt Q6ZRQ5

Length
1243 aa
Mass
142.3 kDa
Annotated
2026-04-28
16 papers in source corpus 12 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MMS22L is a genome maintenance factor that forms an obligate heterodimer with TONSL and functions as a recombination mediator at stressed replication forks, while also contributing to sister chromatid cohesion and interstrand crosslink repair. The MMS22L-TONSL complex is recruited to post-replicative chromatin through TONSL's ankyrin repeat domain reading H4K20me0 on newly deposited histones, with ASF1/CAF-1-dependent chromatin assembly further facilitating recruitment to ssDNA at damaged forks (PMID:27338793, PMID:29478807). MMS22L directly binds RAD51 and, together with TONSL, stimulates RAD51-ssDNA nucleofilament formation while limiting RAD51 assembly on dsDNA, thereby promoting homologous recombination-mediated fork restart in a manner analogous to BRCA2 (PMID:27797818, PMID:21055983). MMS22L-TONSL additionally facilitates ESCO2 recruitment for sister chromatid cohesion establishment and recruits FANCM and the Fanconi anemia core complex to enable interstrand crosslink repair (PMID:36622344); impaired nuclear import of MMS22L due to defective CDAN1-IPO4 interaction is linked to congenital dyserythropoietic anemia type I (PMID:41446536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2010 High

    The discovery that MMS22L forms a stable complex with TONSL and is required for RAD51 foci formation and homologous recombination at collapsed replication forks established MMS22L as a core genome maintenance factor, resolving what its mammalian function was after identification of the yeast ortholog.

    Evidence Three simultaneous studies using Co-IP, RNAi depletion, RAD51 foci assays, HR reporters, and camptothecin sensitivity in human cells

    PMID:21055983 PMID:21055984 PMID:21055985

    Open questions at the time
    • Mechanism by which MMS22L-TONSL promotes RAD51 loading was not defined
    • How MMS22L-TONSL is recruited to damaged forks was unknown
    • Whether MMS22L directly contacts RAD51 or acts indirectly was unresolved
  2. 2010 Medium

    Identification of interactions between MMS22L-TONSL and the FACT and MCM complexes, and demonstration that MMS22L loss leads to CtIP-dependent RPA loading and ATR-CHK1 activation, placed the complex within the replication-coupled DNA damage response and suggested a role upstream of checkpoint signaling.

    Evidence AP-MS, RNAi with chromatin fractionation and signaling analysis in human cells

    PMID:21055985 PMID:21113133

    Open questions at the time
    • Functional significance of FACT and MCM interactions for MMS22L activity was not tested
    • Whether Cul4-dependent degradation of MMS22L upon replication stress is regulatory or incidental was unclear
  3. 2012 Medium

    Demonstrating that TONSL binding is required for MMS22L nuclear localization and protein stability resolved how MMS22L reaches its site of action and explained why the two subunits are co-dependent.

    Evidence siRNA knockdown, exogenous expression, nuclear fractionation, and Co-IP in human cancer cells

    PMID:22895565

    Open questions at the time
    • Which domain of MMS22L mediates TONSL binding was not mapped
    • Whether MMS22L contributes reciprocally to TONSL stability was not addressed
  4. 2016 High

    Structural and biochemical reconstitution revealed that TONSL's ARD reads H4K20me0 on newly deposited histones, providing the molecular basis for how MMS22L-TONSL is specifically recruited to post-replicative chromatin and explaining the S-phase specificity of complex function.

    Evidence Crystal structure of TONSL ARD–H4 peptide complex, histone binding assays, ChIP, mutagenesis with functional rescue in human cells

    PMID:27338793

    Open questions at the time
    • Whether additional chromatin marks modulate H4K20me0 recognition was not explored
    • How H4K20me0 reading is coordinated with ssDNA engagement at damaged forks remained unclear
  5. 2016 High

    In vitro reconstitution demonstrated that MMS22L directly binds RAD51 and that MMS22L-TONSL stimulates RAD51-ssDNA filament formation while suppressing RAD51 assembly on dsDNA, establishing the complex as a bona fide recombination mediator analogous to BRCA2.

    Evidence Biochemical reconstitution with purified recombinant proteins, strand exchange assay, ssDNA binding assay, replication fork reversal assay

    PMID:27797818

    Open questions at the time
    • Structural basis for MMS22L-RAD51 interaction was not determined
    • Whether MMS22L-TONSL and BRCA2 act redundantly or in distinct contexts in vivo was unclear
  6. 2018 High

    Showing that ASF1- and CAF-1-dependent chromatin assembly is a prerequisite for MMS22L-TONSL recruitment to damaged forks linked the histone chaperone pathway to recombination mediator loading and explained how newly assembled chromatin signals for repair.

    Evidence RNAi of ASF1/CAF-1, RAD51/RPA foci assays, chromatin fractionation, DNA-PKcs kinase assay for ASF1A phosphorylation in human cells

    PMID:29478807

    Open questions at the time
    • Whether the requirement reflects H4K20me0 deposition by chaperones or a distinct mechanism was not fully dissected
    • The role of DNA-PKcs phosphorylation of ASF1A in physiological contexts beyond exogenous damage was not tested
  7. 2022 Medium

    Genome-wide CRISPR screening revealed that MMS22L-TONSL functions in sister chromatid cohesion establishment by facilitating ESCO2 recruitment to forks, expanding the complex's role beyond HR to a parallel cohesion pathway synthetic lethal with DSCC1-RFC.

    Evidence CRISPR screens, genetic epistasis in DSCC1-KO cells combined with MMS22L depletion, SCC assays, Co-IP for ESCO2 in human cells

    PMID:36622344

    Open questions at the time
    • Whether MMS22L directly contacts ESCO2 or acts through TONSL was not resolved
    • Whether the cohesion function is independent of or coupled to the HR function was unclear
  8. 2025 Medium

    Identification of MMS22L within a CDAN1-containing complex whose nuclear import depends on importin 4 linked MMS22L deficiency to congenital dyserythropoietic anemia type I, revealing a disease-relevant mechanism in which impaired nuclear import of MMS22L causes erythroid proliferation and differentiation arrest.

    Evidence Co-IP, nuclear fractionation, zebrafish haploinsufficiency model, siRNA in human erythroid progenitors, whole exome sequencing of CDAI patients

    PMID:41446536

    Open questions at the time
    • Whether MMS22L is a direct CDAN1 binding partner or an indirect member of the complex was not resolved
    • The precise mechanism by which MMS22L loss causes p53 activation and epigenetic alterations in erythroid cells is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the MMS22L-TONSL heterodimer and its interface with RAD51, whether the HR, cohesion, and ICL repair functions are mechanistically coupled or separable, and how MMS22L-TONSL activity is coordinated with BRCA2 and the anti-recombinase FIGNL1 in vivo.
  • No high-resolution structure of full-length MMS22L-TONSL or its complex with RAD51 exists
  • Separation-of-function mutations distinguishing HR from cohesion roles have not been generated
  • In vivo epistasis between MMS22L-TONSL and BRCA2 in physiological HR contexts remains undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-69306 DNA Replication 2 R-HSA-1640170 Cell Cycle 1
Partners
ASF1ACDAN1ESCO2RAD51RPATONSL
Complex memberships
MMS22L-TONSL heterodimer

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 MMS22L 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 after DNA damage and homologous recombination-mediated repair of stalled or collapsed replication forks. Co-immunoprecipitation, RNAi depletion with RAD51 foci assay, camptothecin sensitivity assay, HR reporter assay Molecular cell High 21055983 21055984 21055985
2010 MMS22L-TONSL interacts with the FACT (facilitator of chromatin transcription) and MCM (minichromosome maintenance) complexes, and cells depleted of MMS22L load phosphorylated RPA onto chromatin in a CtIP-dependent manner, activating ATR/ATRIP-CHK1 and DSB repair signaling pathways. Mass spectrometry-based affinity purification, RNAi depletion with chromatin fractionation and signaling pathway analysis Molecular cell Medium 21055985
2010 Human MMS22L is degraded in a Cul4-dependent manner upon replication stress, unlike yeast Mms22 which binds stably to Cul4; MMS22L physically interacts with NFKBIL2/TONSL which co-purifies with histones, chromatin remodelling factors, and DNA replication/repair factors. RNAi screen, live-cell imaging, co-purification/mass spectrometry, immunoblot for protein stability The EMBO journal Medium 21113133
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 reduces nuclear MMS22L levels and suppresses cancer cell growth. siRNA knockdown, exogenous expression, nuclear fractionation, co-immunoprecipitation International journal of oncology Medium 22895565
2016 The MMS22L-TONSL heterodimer directly interacts with RPA-coated ssDNA; MMS22L directly binds RAD51, and MMS22L-TONSL stimulates RAD51-ssDNA nucleoprotein filament formation and RAD51-dependent strand exchange activity in vitro by limiting RAD51 assembly on dsDNA, analogous to BRCA2. In vitro biochemical reconstitution with recombinant proteins, strand exchange assay, ssDNA-binding assay, Co-IP in human cells, replication fork reversal assay The EMBO journal High 27797818
2016 The TONSL ankyrin repeat domain (ARD) reads histone H4 tails unmethylated at K20 (H4K20me0), a mark specific to new histones incorporated during DNA replication, thereby recruiting TONSL-MMS22L to post-replicative chromatin; TONSL ARD mutants unable to read H4K20me0 fail to accumulate at challenged replication forks and cause genome instability and cell death. Crystal structure of TONSL ARD with H4 peptide, histone peptide binding assays, ChIP, live-cell imaging, mutagenesis of TONSL ARD with functional rescue assays Nature High 27338793
2018 MMS22L-TONSL recruitment to ssDNA during homologous recombination depends on the histone chaperones ASF1 and CAF-1; blocking chromatin assembly by ASF1 or CAF-1 knockdown or ASF1A mutants unable to bind histones reduces MMS22L-TONSL recruitment, impairing RAD51 loading and causing persistent RPA foci and ATR-Chk1 activation. Additionally, DNA-PKcs-dependent phosphorylation of ASF1A upon DNA damage enhances chromatin assembly and promotes MMS22L-TONSL recruitment. RNAi knockdown of ASF1/CAF-1, RAD51/RPA foci immunofluorescence, chromatin fractionation, kinase assay for ASF1A phosphorylation, co-immunoprecipitation Molecular cell High 29478807
2022 MMS22L-TONSL functions in sister chromatid cohesion (SCC) establishment in a pathway parallel to DSCC1-RFC; MMS22L-TONSL facilitates ESCO2 recruitment to replication forks, and synthetic lethality between DSCC1 and MMS22L results from detrimental SCC loss. Genome-wide CRISPR screens, genetic epistasis (DSCC1-KO combined with MMS22L depletion), SCC assays, co-immunoprecipitation for ESCO2 recruitment Life science alliance Medium 36622344
2025 MMS22L and CDAN1 are part of the same protein complex whose nuclear import is mediated by importin 4 (IPO4); MMS22L nuclear import is impaired in congenital dyserythropoietic anemia type I (CDAI) patients due to defective interaction between CDAN1 and IPO4. Loss of MMS22L in human erythroid progenitors causes proliferation and differentiation arrest associated with p53 pathway activation and global epigenetic alterations. Co-immunoprecipitation, nuclear fractionation, zebrafish haploinsufficiency model, siRNA knockdown in human erythroid progenitors, whole exome sequencing HemaSphere Medium 41446536
2025 TONSL-MMS22L heterodimer and FANCM form an interdependent complex on chromatin upon replication stress; TONSL-MMS22L recruits FANCM and the Fanconi anemia (FA) core complex to stalled/collapsed forks, promotes FANCD2 monoubiquitination, and facilitates repair and replication traverse of DNA interstrand crosslinks. Reciprocally, FANCM DNA translocase activity and phosphorylation facilitate recruitment of TONSL-MMS22L and RAD51 to perturbed forks. Co-immunoprecipitation, chromatin fractionation, FANCD2 ubiquitination assay, ICL repair assay, sister chromatid exchange assay, RNAi depletion bioRxivpreprint Medium 41030968
2024 The MMS22L-TONSL complex interacts with FIGNL1 (an anti-recombinase that dissociates RAD51 filaments) and is critical for homologous recombination in BRCA2/FIGNL1 double-deficient cells, placing MMS22L-TONSL in a pathway that counteracts FIGNL1-mediated RAD51 removal. Co-immunoprecipitation, genetic epistasis in BRCA2/FIGNL1 double-deficient mouse embryonic stem cells, HR assay bioRxivpreprint Low bio_10.1101_2024.11.03.621741

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 174 27338793
2010 The MMS22L-TONSL complex mediates recovery from replication stress and homologous recombination. Molecular cell 120 21055983
2010 A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Molecular cell 106 21055985
2010 Identification of the MMS22L-TONSL complex that promotes homologous recombination. Molecular cell 100 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 79 29478807
2016 The MMS22L-TONSL heterodimer directly promotes RAD51-dependent recombination upon replication stress. The EMBO journal 73 27797818
2010 RNAi-based screening identifies the Mms22L-Nfkbil2 complex as a novel regulator of DNA replication in human cells. The EMBO journal 68 21113133
2012 Identification of a novel oncogene, MMS22L, involved in lung and esophageal carcinogenesis. International journal of oncology 20 22895565
2022 MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC. Life science alliance 13 36622344
2021 The SOX9-MMS22L Axis Promotes Oxaliplatin Resistance in Colorectal Cancer. Frontiers in molecular biosciences 10 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 3 34660277
2022 Integrative pan-cancer landscape of MMS22L and its potential role in hepatocellular carcinoma. Frontiers in genetics 2 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