Affinage

MSL1

Male-specific lethal 1 homolog · UniProt Q68DK7

Length
614 aa
Mass
67.1 kDa
Annotated
2026-06-10
26 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSL1 is the central scaffold of the MSL histone acetyltransferase complex that drives X-chromosome dosage compensation in male Drosophila, decorating hundreds of X-linked sites in a sex-specific manner and acting interdependently with MSL2, MSL3, MLE and H4K16 acetylation (PMID:8325488, PMID:8562424, PMID:10619853). As a scaffold, MSL1 uses spatially distinct regions: an N-terminal basic motif that recognizes ~30 high-affinity X-chromosomal sites and engages roX noncoding RNA, a glycine-rich motif that mediates MSL1 self-association, and a leucine-zipper-like motif that binds MSL2, while its C-terminal region co-purifies with MSL3 and the acetyltransferase MOF/KAT8 (PMID:10619853, PMID:16199870, PMID:39699942). Crystal structures define these interfaces and show that MSL2 binds only an MSL1 dimer, with MSL1 dimerization being essential for complex targeting to and spreading along X-linked gene bodies, whereas promoter binding is dimerization- and partner-independent (PMID:21217699, PMID:23084835). The MSL1/MSL2 module also carries MSL2-dependent enzymatic outputs: MSL1 is a substrate for MSL2 E3 ubiquitin ligase activity, and the purified MSL1/MSL2 complex ubiquitylates histone H2B at K34 on free histone substrates (PMID:23084835, PMID:30930284). MSL1 couples chromatin modification to transcription by interacting with CDK7/TFIIH to promote RNA Pol II Ser5 phosphorylation, and its own phosphorylation state controls MOF localization and H4K16 acetylation (PMID:27183194). In mammals MSL1 retains MOF binding and H4K16-acetylation activity, localizes to sub-nuclear foci via two NLS, and forms liquid-liquid phase-separation condensates with STAT3 or histone H4 that concentrate acetyl-CoA to promote STAT3 K685 and H4K16 acetylation during liver regeneration (PMID:17335777, PMID:24913909, PMID:37279389). MSL1 is additionally recruited to the nucleus upon DNA damage where it binds damaged DNA and Nupr1 to support cell survival (PMID:24205110).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1993 Medium

    Established that MSL1 is a chromatin-associated factor acting specifically in males, linking it to X-linked transcriptional upregulation.

    Evidence Sex-specific immunostaining of MSL1 along the X chromosome in Drosophila nuclei

    PMID:8325488

    Open questions at the time
    • Did not define molecular partners or mechanism of X recognition
    • No biochemical demonstration of a complex
  2. 1995 Medium

    Showed MSL1 functions within a mutually dependent multi-subunit assembly, not as an isolated factor, by demonstrating reciprocal localization requirements with MSL2, MSL3, MLE and H4K16ac.

    Evidence Immunostaining in msl mutant backgrounds across embryogenesis

    PMID:8062831 PMID:8562424 PMID:9409833

    Open questions at the time
    • Interdependence was genetic/localization-based, not direct biochemical contact mapping
    • Order of assembly unresolved
  3. 1998 Medium

    Defined how MSL1 dosage is restricted to males, identifying post-translational instability and reduced synthesis as the controls preventing female complex assembly.

    Evidence Western quantification and co-overexpression genetics in Drosophila

    PMID:9755201

    Open questions at the time
    • Molecular machinery of female-specific instability not identified
    • Did not link to ubiquitylation directly
  4. 2000 High

    Established MSL1 as the scaffold by mapping an N-terminal MSL2-binding region and a C-terminal region that co-purifies with MSL3 and MOF, giving the complex a modular architecture.

    Evidence FLAG/GST pulldowns, co-IP, and dominant-negative domain overexpression in Drosophila

    PMID:10619853

    Open questions at the time
    • Domain boundaries were coarse without structural detail
    • Stoichiometry not defined
  5. 2005 High

    Resolved the N-terminus into three functional motifs, separating high-affinity-site DNA binding, self-association, and MSL2 binding.

    Evidence In vitro self-association, co-IP, and transgenic localization of N-terminal fragments with mutagenesis

    PMID:16199870

    Open questions at the time
    • Did not establish how self-association couples to spreading at atomic resolution
  6. 2007 Medium

    Defined the chromatin-binding behavior and partner repertoire, showing MSL-1 binding does not strictly predict transcriptional output and identifying mammalian MSL1 interactors including MOF and TTC4.

    Evidence ChIP-chip on the male X; yeast two-hybrid with in vitro pulldown confirmation

    PMID:16547175 PMID:17335777

    Open questions at the time
    • Additional determinants of dosage-compensated status not identified
    • Functional relevance of several Y2H interactors untested
  7. 2012 High

    Provided structural mechanism: MSL1 dimerizes independently of MSL2, MSL2 binds only the dimer, and dimerization is required for targeting and spreading along gene bodies but not promoter binding; also identified MSL1 as an MSL2 ubiquitylation substrate.

    Evidence X-ray crystallography of MSL1/MSL2 and MSL1/MSL3 and MSL1/MOF interfaces, structure-based mutagenesis, ChIP, in vitro ubiquitylation

    PMID:21217699 PMID:23084835

    Open questions at the time
    • Functional consequence of MSL1 ubiquitylation in vivo unresolved
    • How dimerization drives spreading mechanistically not fully defined
  8. 2013 Medium

    Extended MSL1 function into the DNA-damage response, showing it binds damaged DNA and Nupr1 to support survival under genotoxic stress.

    Evidence ITC, NMR, fluorescence binding, nuclear co-localization and cell viability under cisplatin

    PMID:24205110

    Open questions at the time
    • Link to the canonical MSL acetyltransferase function unclear
    • Downstream repair pathway not defined
  9. 2016 High

    Connected MSL1 to transcriptional machinery and its own regulation, showing it engages CDK7/TFIIH to promote Pol II Ser5 phosphorylation and that MSL1 phosphorylation controls MOF localization and H4K16ac.

    Evidence Genetic/biochemical interaction, phospho-Pol II ChIP, transgenic phosphomutant Drosophila across two species

    PMID:27183194

    Open questions at the time
    • Kinase responsible in vivo not pinned down in this study
    • Direct CDK7 contact interface unmapped
  10. 2019 Medium

    Demonstrated an intrinsic enzymatic output of the MSL1/MSL2 module, ubiquitylating H2BK34 with strong dependence on substrate configuration.

    Evidence In vitro ubiquitylation with purified proteins and nucleosome gel-shift

    PMID:30930284

    Open questions at the time
    • Poor activity on intact nucleosomes leaves physiological substrate unclear
    • Single in vitro study
  11. 2021 Medium

    Identified PBK as a kinase that phosphorylates MSL1 to enhance complex assembly and target-gene activation, while a separate Drosophila study showed certain phosphosites are dispensable for dosage compensation.

    Evidence Co-IP/ChIP/phosphorylation assays in carcinoma cells; transgenic phosphomutant immunostaining in Drosophila

    PMID:33431797 PMID:34426916

    Open questions at the time
    • Which specific MSL1 residues mediate context-dependent effects not reconciled across systems
    • Generality of PBK regulation beyond cancer cells untested
  12. 2023 Medium

    Revealed a phase-separation mechanism in mammals, with MSL1 condensates concentrating acetyl-CoA to promote STAT3 and H4K16 acetylation during liver regeneration.

    Evidence Phase separation and acetylation assays, co-IP, partial hepatectomy mouse model

    PMID:37279389

    Open questions at the time
    • Condensate composition relative to canonical MSL complex undefined
    • Sequence determinants of MSL1 phase separation unmapped
  13. 2024 High

    Established that the extreme MSL1 N-terminus mediates roX2 RNA binding required for complex co-binding at high-affinity sites, distinguishing RNA-dependent HAS recruitment from RNA-independent promoter binding.

    Evidence Transgenic MSL1 substitution mutants with ChIP, immunostaining, and RNA immunoprecipitation

    PMID:39699942

    Open questions at the time
    • Structural basis of MSL1 N-terminus/roX2 contact not determined
    • How RNA binding integrates with dimerization-driven spreading unresolved
  14. 2025 Low

    Proposed an MSL1 role in ferroptosis via negative regulation of KCTD12 and the SLC7A11 axis in colon cancer.

    Evidence Knockdown/overexpression with ROS, GSH, MDA and ferroptosis assays

    PMID:40221412

    Open questions at the time
    • No direct molecular mechanism linking MSL1 to KCTD12 established
    • Single lab, indirect readouts only

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the canonical MSL acetyltransferase scaffold function integrates with the mammalian-specific activities (DNA-damage response, phase separation, ferroptosis regulation) into a unified model remains unresolved.
  • No structural model of the full mammalian complex with RNA
  • Physiological H2BK34 ubiquitylation context undefined
  • Mechanistic link between condensate formation and chromatin targeting unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0003677 DNA binding 2 GO:0003723 RNA binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CDK7KAT8/MOFMLEMSL2MSL3NUPR1PBKSTAT3
Complex memberships
MSL complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 MSL1 protein associates with hundreds of sites along the length of the X chromosome in male (but not female) nuclei, consistent with a direct role in increasing X-linked gene transcription in males. Immunostaining/chromosome localization assay Genetics Medium 8325488
1994 X-chromosomal association of MSL-1 depends on wild-type function of the other MSL proteins (MLE, MSL-2, MSL-3), indicating MSL-1 participates in a multi-subunit complex; binding is negatively regulated by the master sex-determination gene Sxl. Genetic analysis; immunostaining in mutant backgrounds The EMBO journal Medium 8062831
1995 MSL-1, MSL-2, MLE, and histone H4Ac16 are mutually interdependent for sub-nuclear (X chromosome) localization from early embryogenesis; loss of any one MSL protein abolishes co-localization of the others. Immunostaining of embryos in msl mutant backgrounds Mechanisms of development Medium 8562424
1997 MSL-2 binding to the X chromosome depends on MSL-1; the two proteins co-localize precisely, suggesting they function together to associate with the X. The MSL-2 RING finger domain is essential for MSL-2 function in this complex. Immunostaining in msl mutant backgrounds; EMS suppressor screen; site-directed mutagenesis of MSL-2 Genetics Medium 9409833
1998 MSL1 protein abundance in females is reduced compared to males through two mechanisms: predominantly post-translational protein instability and secondarily reduced protein synthesis. Overcoming both controls by co-overexpressing MSL1 and MSL2 in females causes 100% female-specific lethality. Western blot quantification; overexpression genetics in Drosophila Genetics Medium 9755201
2000 MSL1 serves as a scaffold for MSL complex assembly: its N-terminal domain interacts with MSL2, and its C-terminal domain co-purifies with both MSL3 and MOF (histone acetyltransferase). Dominant-negative overexpression of either domain causes male-specific lethality, and the C-terminal domain shows similarity to the transcription co-activator CBP. FLAG affinity purification; GST pulldown; co-immunoprecipitation with HA-tagged MSL3; dominant-negative overexpression genetics The EMBO journal High 10619853
2005 The N-terminal region of Drosophila MSL1 contains three functionally distinct motifs: (1) a basic motif required for binding to ~30 high-affinity X-chromosomal sites; (2) a glycine-rich motif mediating MSL1 self-association in vitro and binding to the assembled MSL complex; (3) a leucine zipper-like motif that binds MSL2 and is required for X chromosome association. In vitro self-association assay; co-immunoprecipitation; immunostaining of transgenic flies expressing N-terminal domain fragments; site-directed mutagenesis Molecular and cellular biology High 16199870
2006 ChIP-chip analysis reveals MSL-1 binding profile across the male X chromosome; MSL-1 binding does not strictly correlate with transcriptional output of target genes, suggesting additional factors determine dosage-compensated status beyond direct MSL-1 binding. Chromatin immunoprecipitation coupled with DNA microarray (ChIP-chip) Genes & development Medium 16547175
2007 Incorporation of roX noncoding RNAs into the MSL complex alters its chromatin-binding specificity. The amino-terminal RING finger domain of MSL2, acting as a complex with MSL1, mediates binding to the heterochromatic chromocenter and a few chromosomal arm sites; this requires the same basic motif of MSL1 needed for high-affinity X-chromosomal binding. Transgenic expression of MSL2 domain fragments; immunostaining; co-immunoprecipitation Molecular and cellular biology Medium 18086881
2007 Mammalian MSL1 (hampin) interacts with MYST1/MOF, TTC4, KIAA0103, NOP17, and transcription factor GCBP as identified by yeast two-hybrid; the majority of interactions were confirmed by in vitro pulldown of bacterially expressed proteins. Yeast two-hybrid screen; in vitro pulldown assay Biochemical and biophysical research communications Medium 17335777
2011 Crystal structures of mammalian MSL1 binary complexes with MSL3 and MOF reveal: MSL1 interacts with MSL3 as an extended chain forming an extensive hydrophobic interface; the MSL1-MOF interface involves electrostatic interactions between the MOF HAT domain and a long helix of MSL1. Selective disruption of Msl1-Msl3 or Msl1-Mof interactions in Drosophila severely impairs MSL complex targeting to gene bodies and high-affinity sites without affecting promoter binding. X-ray crystallography; structure-based mutagenesis; ChIP in Drosophila Nature structural & molecular biology High 21217699
2012 Crystal structure of the MSL1/MSL2 core shows two MSL2 subunits binding to an MSL1 dimer; MSL1 dimerization is MSL2-independent, but MSL2 can only interact with the MSL1 dimer. Structure-based mutants show Msl1 dimerization is essential for MSL complex targeting to and spreading along X-linked gene bodies. Additionally, MSL1 is a substrate for MSL2 E3 ubiquitin ligase activity. MSL1 binding to promoters is independent of its dimerization status and other MSL proteins. X-ray crystallography; structure-based mutagenesis; ChIP; in vitro ubiquitylation assay Molecular cell High 23084835
2013 Human MSL1 and Nupr1 are recruited to the nucleus in response to DNA damage and form a complex essential for cell survival under cisplatin treatment. MSL1 binds Nupr1 with moderate affinity (Kd ~2.8 µM) in an entropically driven process. MSL1 does not bind undamaged DNA but binds chemically damaged DNA with moderate affinity (~1.2 µM). Biophysical binding assays (ITC, fluorescence); NMR; cell viability assays; nuclear co-localization PloS one Medium 24205110
2014 Mammalian MSL1 contains two distinct nuclear localization signals (NLS): a novel NLS common to all isoforms, and a previously known bipartite NLS in the PEHE domain. Isoforms possessing both NLS localize to sub-nuclear foci and can direct co-chaperone TTC4 there; all isoforms retain the ability to affect H4K16 acetylation. Subcellular localization of MSL1 isoforms; NLS deletion constructs; co-localization with TTC4; H4K16 acetylation assay Journal of cellular biochemistry Medium 24913909
2016 MSL1 interacts functionally with CDK7 (a subunit of the CAK complex of TFIIH); MSL1 depletion leads to decreased Ser5 phosphorylation of RNA polymerase II. MSL1 is itself a phosphoprotein, and transgenic flies expressing MSL1 phosphomutants show mislocalization of MOF and reduced H4K16 acetylation, causing male lethality. Genetic interaction; biochemical interaction assays; phospho-Pol II ChIP; transgenic phosphomutant Drosophila Nature structural & molecular biology High 27183194
2019 Purified MSL1/MSL2 complex ubiquitylates histone H2B (at K34) in vitro in a substrate-configuration-dependent manner; MSL1/2 efficiently ubiquitylates free histone substrates but very poorly modifies intact nucleosomes, implying a requirement for nucleosome structural alteration for efficient H2BK34 ubiquitylation. In vitro ubiquitylation assay with purified proteins; nucleosome gel-mobility shift assay Archives of biochemistry and biophysics Medium 30930284
2021 PBK kinase phosphorylates MSL1 and enhances MSL1 interaction with MSL2, MSL3, and KAT8 (components of the MSL complex). This promotes MSL complex enrichment on the CD276 promoter, leading to increased H4K16 acetylation and CD276 transcriptional activation in nasopharyngeal carcinoma cells. Co-immunoprecipitation; ChIP; phosphorylation assay; knockdown/overexpression in cancer cells; H4K16ac western blot Oncogenesis Medium 33431797
2021 Phosphorylation-site mutations in Drosophila MSL1 (replacing phosphorylatable residues) do not affect specific binding of the dosage compensation complex to the male X chromosome or its functional activity, indicating these particular phosphorylation sites are dispensable for dosage compensation. Transgenic Drosophila expressing MSL1 phosphomutants; immunostaining Doklady. Biochemistry and biophysics Medium 34426916
2023 MSL1 forms liquid-liquid phase separation condensates with STAT3 or histone H4 in hepatocytes, enriching acetyl-CoA (Ac-CoA) in these condensates. Ac-CoA in turn enhances MSL1 condensate formation, synergistically promoting acetylation of STAT3 K685 and H4K16, thereby stimulating liver regeneration after partial hepatectomy. Phase separation assays; co-immunoprecipitation; acetylation assays; partial hepatectomy mouse model; MSL1 knockdown/overexpression Advanced science Medium 37279389
2024 The N-terminal region of Drosophila MSL1 (amino acids 3–7) is critical for interaction with roX2 RNA and for MSL complex binding to high-affinity sites (HAS) on the X chromosome. MSL1GS (N-terminal substitution mutant) binds promoters like wild-type MSL1 but fails to co-bind MSL2 and MSL3 at HAS; overexpression of MSL2 partially restores dosage compensation, indicating roX RNA interaction with MSL1 N-terminus is essential for efficient MSL complex assembly at HAS. Transgenic Drosophila expressing MSL1 deletion/substitution mutants; ChIP; immunostaining; RNA immunoprecipitation eLife High 39699942
2025 MSL1 negatively regulates KCTD12 expression in colon cancer cells; Erastin-induced ferroptosis suppresses MSL1 expression leading to KCTD12 upregulation, which in turn reduces SLC7A11 levels, promoting ferroptosis through altered ROS, GSH, and MDA levels. Knockdown/overexpression studies; biochemical assays for ROS, GSH, MDA; ferroptosis cell death assay Cell death & disease Low 40221412

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Drosophila male-specific lethal-2 protein: structure/function analysis and dependence on MSL-1 for chromosome association. Genetics 127 9409833
1993 The male-specific lethal-one (msl-1) gene of Drosophila melanogaster encodes a novel protein that associates with the X chromosome in males. Genetics 100 8325488
2011 Structural basis for MOF and MSL3 recruitment into the dosage compensation complex by MSL1. Nature structural & molecular biology 95 21217699
2006 X-chromosome-wide profiling of MSL-1 distribution and dosage compensation in Drosophila. Genes & development 75 16547175
2000 MSL1 plays a central role in assembly of the MSL complex, essential for dosage compensation in Drosophila. The EMBO journal 73 10619853
1995 The dosage compensation regulators MLE, MSL-1 and MSL-2 are interdependent since early embryogenesis in Drosophila. Mechanisms of development 64 8562424
2007 Incorporation of the noncoding roX RNAs alters the chromatin-binding specificity of the Drosophila MSL1/MSL2 complex. Molecular and cellular biology 48 18086881
2005 The amino-terminal region of Drosophila MSL1 contains basic, glycine-rich, and leucine zipper-like motifs that promote X chromosome binding, self-association, and MSL2 binding, respectively. Molecular and cellular biology 47 16199870
2013 Deciphering the binding between Nupr1 and MSL1 and their DNA-repairing activity. PloS one 39 24205110
2012 Msl1-mediated dimerization of the dosage compensation complex is essential for male X-chromosome regulation in Drosophila. Molecular cell 38 23084835
1998 Modulation of MSL1 abundance in female Drosophila contributes to the sex specificity of dosage compensation. Genetics 38 9755201
1994 Dosage compensation in Drosophila: the X-chromosomal binding of MSL-1 and MLE is dependent on Sxl activity. The EMBO journal 36 8062831
2021 PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma. Oncogenesis 27 33431797
2021 Shift in MSL1 alternative polyadenylation in response to DNA damage protects cancer cells from chemotherapeutic agent-induced apoptosis. Cell reports 19 34644577
2019 Genetic and physical interactions between the organellar mechanosensitive ion channel homologs MSL1, MSL2, and MSL3 reveal a role for inter-organellar communication in plant development. Plant direct 19 31245767
2016 Functional interplay between MSL1 and CDK7 controls RNA polymerase II Ser5 phosphorylation. Nature structural & molecular biology 18 27183194
1996 Dosage compensation in Drosophila: the X chromosome binding of MSL-1 and MSL-2 in female embryos is prevented by the early expression of the Sxl gene. Mechanisms of development 17 8817458
2007 Characterization of hampin/MSL1 as a node in the nuclear interactome. Biochemical and biophysical research communications 15 17335777
2023 MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 37279389
2012 Pleiotropic roles of the Msi1-like protein Msl1 in Cryptococcus neoformans. Eukaryotic cell 9 23042129
2005 [Tissue specificity of alternative splicing products of mouse mRNA encoding new protein hampin homologous to the Drosophila MSL-1 protein]. Bioorganicheskaia khimiia 9 16119455
2025 Male-specific lethal 1 (MSL1) promotes Erastin-induced ferroptosis in colon cancer cells by regulating the KCTD12-SLC7A11 axis. Cell death & disease 5 40221412
2024 N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation. eLife 4 39699942
2019 Analysis of histone ubiquitylation by MSL1/MSL2 proteins in vitro. Archives of biochemistry and biophysics 4 30930284
2014 Two distinct nuclear localization signals in mammalian MSL1 regulate its function. Journal of cellular biochemistry 4 24913909
2021 Mutations of Phosphorylation Sites in MSL1 Protein Do Not Affect Dosage Compensation in Drosophila melanogaster. Doklady. Biochemistry and biophysics 1 34426916

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