Affinage

MSL2

E3 ubiquitin-protein ligase MSL2 · UniProt Q9HCI7

Audit flag: alt product
Length
577 aa
Mass
62.5 kDa
Annotated
2026-04-28
44 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MSL2 is the organizing subunit of the Drosophila dosage compensation complex (DCC), integrating RING-finger E3 ubiquitin ligase activity, CXC-domain DNA recognition, and lncRNA-dependent chromatin compartmentalization to achieve twofold transcriptional upregulation of the male X chromosome. Its RING finger directly binds MSL1 to nucleate DCC assembly (PMID:9736618), while its CXC domain recognizes MRE motifs through minor-groove contacts by a single arginine, cooperatively recruiting a CXC dimer together with the pioneer factor CLAMP (PMID:25452275, PMID:37602401); its low-complexity C-terminal domain cooperates with roX lncRNAs to form a condensed X-chromosomal compartment (PMID:33208948). MSL2 also functions as an E3 ligase that ubiquitylates histone H2B at K34 (stimulating H3 K4/K79 methylation in trans), auto-ubiquitylates itself and MSL partners for proteasomal homeostasis, and in mammals ubiquitylates 53BP1 and APOBEC3B (PMID:21726816, PMID:23084834, PMID:23874665). In females, MSL2 production is suppressed at three post-transcriptional levels — SXL blocks splicing by preventing U1 and U2AF recruitment, SXL–HOW retain msl2 mRNA in the nucleus, and SXL together with UNR, Hrp48, and PABP prevents 40S ribosomal subunit association — ensuring sex-specific dosage compensation (PMID:10617208, PMID:23788626, PMID:19941818, PMID:39504588).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Identifying MSL2 as the limiting, sex-specific organizer of the DCC answered how the dosage compensation machinery is restricted to males and how the complex assembles on the X chromosome.

    Evidence Co-IP from male larval extracts, ectopic MSL2 expression in females driving DCC assembly on female X chromosomes, immunolocalization on polytene chromosomes

    PMID:7588059 PMID:7781064 PMID:8562424

    Open questions at the time
    • Mechanism of X-chromosomal targeting not yet defined
    • Direct interaction surfaces between MSL2 and other MSL subunits unknown
  2. 1998 High

    Demonstrating that the MSL2 RING finger directly binds MSL1 and that point mutations disrupt this interaction and male viability established the molecular basis for DCC nucleation.

    Evidence Yeast two-hybrid, Co-IP, chromatographic co-fractionation, site-directed mutagenesis of RING finger zinc-binding residues

    PMID:9736618

    Open questions at the time
    • Structural basis of the RING–MSL1 interface not resolved at atomic level
    • How roX RNAs contribute to complex maturation unknown
  3. 1999 High

    Reconstituting SXL-mediated splicing inhibition and translational repression of msl-2 in vitro revealed the dual UTR mechanism that silences MSL2 in females: SXL blocks U2AF at the 3' splice site and prevents 40S ribosomal subunit recruitment via both UTRs.

    Evidence In vitro splicing assays with UV crosslinking and splice-site mutagenesis; cell-free Drosophila embryo translation system

    PMID:10545124 PMID:10617208

    Open questions at the time
    • Trans-acting co-repressors recruited by SXL not yet identified
    • Mechanism of 5' UTR-mediated repression unclear
  4. 2003 High

    Pinpointing that SXL prevents stable 40S subunit association with msl-2 mRNA defined the precise step of translation initiation that is blocked, and identification of SXL's repressor domain showed it recruits co-repressors to the 3' UTR.

    Evidence Ribosome association assays on sucrose gradients, tethering assays, UV-crosslinking

    PMID:12769862 PMID:14532129

    Open questions at the time
    • Identity of 3' UTR co-repressor proteins unknown
    • Contribution of 5' UTR intron retention versus translational repression not quantified in vivo
  5. 2006 High

    Identifying UNR as a SXL-recruited co-repressor at the msl-2 3' UTR resolved how a ubiquitous protein acquires sex-specific function and provided the first trans-acting partner in the translational silencing complex.

    Evidence mRNP purification with mass spectrometry, Co-IP, RNAi depletion, reporter assays

    PMID:16452508

    Open questions at the time
    • How UNR mechanistically inhibits ribosome recruitment unknown
    • Whether additional co-repressors participate not yet tested
  6. 2007 High

    Domain dissection of MSL2 in vivo revealed that the RING finger suffices for chromocenter binding while the C-terminal proline-rich/basic region is required for X-chromosomal spreading and roX RNA incorporation, separating DCC assembly from targeting.

    Evidence GFP-fusion domain deletions with polytene chromosome localization

    PMID:18086881

    Open questions at the time
    • Whether the C-terminal domain contacts DNA directly unknown
    • How roX RNA incorporation changes binding specificity not mechanistically resolved
  7. 2009 High

    Demonstrating that the SXL–UNR complex operates through PABP to block ribosome recruitment after eIF4E/G loading completed the mechanistic pathway of 3' UTR-mediated translational repression of msl-2.

    Evidence Reconstituted in vitro translation with PABP interaction assays and ribosome recruitment biochemistry

    PMID:19941818

    Open questions at the time
    • Role of the poly(A) tail in 5' UTR-mediated repression not addressed
    • Structural basis of SXL–UNR–PABP ternary complex unknown
  8. 2010 High

    Establishing that the CXC domain directly binds DNA with low nanomolar affinity and is required for faithful X-chromosomal targeting provided the first evidence that MSL2 itself is a sequence-specific DNA-binding factor.

    Evidence Recombinant CXC domain DNA-binding assays, in vivo reporter and GFP localization

    PMID:20139418

    Open questions at the time
    • Target sequence specificity not defined
    • Structure of CXC–DNA complex unknown
  9. 2011 High

    Discovering that human MSL1/MSL2 ubiquitylates H2B at K34 and that this mark stimulates H3 K4/K79 methylation extended MSL2 function from a structural organizer to an enzymatic writer of a histone crosstalk pathway conserved from flies to mammals.

    Evidence In vitro nucleosomal ubiquitylation, mass spectrometry site mapping, ChIP and transcription assays at HOXA9/MEIS1

    PMID:21726816

    Open questions at the time
    • In vivo genome-wide distribution of H2B K34ub not mapped
    • Whether H2B K34ub is essential for dosage compensation not tested
  10. 2012 High

    Showing that MSL2 auto-ubiquitylates and ubiquitylates excess MSL1 for proteasomal degradation revealed a homeostatic quality-control mechanism that maintains correct DCC stoichiometry, and the NMR structure of the CXC domain uncovered an unusual Zn3Cys9 cluster with pre-SET homology.

    Evidence In vitro ubiquitylation with MS site mapping and proteasome inhibitor experiments; NMR structure of CXC domain

    PMID:23029009 PMID:23084834

    Open questions at the time
    • Whether ubiquitylation-mediated turnover is regulated during development unknown
    • CXC–DNA recognition mode not yet structurally resolved
  11. 2013 High

    Identification of SXL–HOW-mediated nuclear retention of msl-2 mRNA established a third layer of female-specific repression beyond splicing and translation, and a role for mammalian MSL2 in NHEJ via 53BP1 ubiquitylation broadened MSL2 function to the DNA damage response.

    Evidence GRAB purification/RNAi/nuclear fractionation for HOW; DT40 KO and human RNAi for NHEJ

    PMID:23788626 PMID:23874665

    Open questions at the time
    • How HOW nuclear retention intersects with splicing and translation repression quantitatively unknown
    • 53BP1 K1690 ubiquitylation not validated by structural or reconstitution approaches
  12. 2014 High

    The crystal structure of the CXC domain bound to DNA showed that a single arginine reads MRE dinucleotide sequences from the minor groove and that the MRE core contains two binding sites on opposite strands that cooperatively recruit a CXC dimer, providing the atomic mechanism for X-chromosomal recognition.

    Evidence Crystal structures of CXC–DNA complexes (specific and nonspecific), mutagenesis, in vivo localization

    PMID:25452275

    Open questions at the time
    • How CXC dimer cooperativity integrates with MSL1 scaffolding and roX RNA in full DCC not known
    • Contribution of non-MRE binding sites to spreading not addressed
  13. 2019 High

    Demonstrating that MSL2 and CLAMP bind MREs cooperatively through a direct physical interaction — and that disrupting this converts cooperativity to competition — revealed a redundant, two-factor recognition logic for DCC targeting to the X chromosome.

    Evidence Genetic double-mutant epistasis (CBD + CXC), reconstituted chromatin binding, CUT&RUN

    PMID:31320325 PMID:37602401

    Open questions at the time
    • Structural basis of MSL2–CLAMP cooperative DNA binding not resolved
    • Whether CLAMP cooperativity operates at all genomic MREs or a subset unknown
  14. 2020 High

    Showing that the MSL2 low-complexity CTD and roX lncRNAs together form a condensed compartment sufficient to drive X-chromosome-specific compartmentalization — even when ectopically transferred to mammalian cells — established phase-separation-like principles as the basis for chromosome-wide dosage compensation.

    Evidence Domain-swap experiments between Drosophila and mammalian MSL2 in both systems, condensate/phase-separation assays

    PMID:33208948

    Open questions at the time
    • Whether the CTD–roX compartment exhibits liquid-liquid phase separation properties in vivo not formally tested
    • How condensation integrates with gene-level transcriptional output unknown
  15. 2024 High

    Structural and biophysical characterization of Hrp48 binding to the msl-2 3' UTR defined the full four-factor repressor assembly (SXL–UNR–Hrp48–PABP), while domain analysis showed the MSL2 B-domain promotes auto-degradation and the P-domain stimulates roX2 transcription.

    Evidence NMR/ITC for Hrp48–RNA interface; domain deletion and stability assays for B-/P-domains

    PMID:38831503 PMID:39504588

    Open questions at the time
    • How Hrp48-mediated SXL stabilization operates at the structural level unknown
    • Relative contribution of B-domain auto-degradation versus chromatin-level homeostasis not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Open questions remain regarding how MSL2's enzymatic (H2B K34ub), DNA-binding (CXC), CLAMP-cooperative, and condensation (CTD–roX) activities are coordinated in real time during DCC assembly and spreading along the X chromosome, and whether mammalian MSL2 functions primarily as a histone ubiquitin ligase or retains a chromosome-scale organizational role.
  • No time-resolved in vivo reconstitution of full DCC assembly exists
  • Mammalian MSL2 chromatin targets beyond HOXA9/MEIS1 not comprehensively mapped
  • Structural model of full DCC on chromatin not available

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0003677 DNA binding 4 GO:0016874 ligase activity 3
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 3
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 GO:0003677 DNA binding 2 R-HSA-73894 DNA Repair 1
Partners
CLAMPHRP48MLEMOFMSL1MSL3SXLUNR
Complex memberships
Drosophila dosage compensation complex (MSL/DCC)MSL1/MSL2 E3 ubiquitin ligase complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 MSL2 (male-specific lethal-2) is a RING finger protein required for X chromosome dosage compensation in Drosophila males; it colocalizes with other MSL proteins on the male X chromosome and coimmunoprecipitates with MSL1 from male larval extracts, indicating it forms a dosage compensation protein complex. Ectopic expression of MSL2 in females causes assembly of the other MSL proteins on female X chromosomes, demonstrating MSL2 is the limiting/organizing subunit. Coimmunoprecipitation, ectopic expression in females, immunolocalization on polytene chromosomes Cell High 7781064
1995 MSL2 protein is not produced in females; sex-specific regulation is mediated through sequences in both the 5' and 3' UTRs of msl-2 mRNA, and msl-2 pre-mRNA is alternatively spliced in a Sex-lethal (SXL)-dependent fashion in its 5' UTR. MSL2 binding to the X chromosome requires the other three MSL proteins. Molecular cloning, reporter assays, polytene chromosome immunostaining in msl mutants Development High 7588059
1995 MSL2, MSL1, and MLE are interdependent for sub-nuclear (X chromosome) localization beginning in early embryogenesis; loss of any one MSL protein abolishes the co-localization of the others and of histone H4Ac16 on the male X. Immunofluorescence on embryos, genetic loss-of-function Mechanisms of development High 8562424
1997 SXL represses MSL2 protein production in females by acting synergistically through sequences in both the 5' and 3' UTRs of msl-2 mRNA, operating directly at the level of translation (not merely splicing). Reporter assays in vivo, genetic epistasis Cell High 9182767
1998 MSL1, MSL2, and MSL3 associate in a complex (by co-immunoprecipitation and chromatography); MSL2 interacts directly with MSL1 through residues clustered around the first zinc-binding site of the RING finger domain. Missense mutations in this region disrupt MSL2–MSL1 interaction and fail to support male viability. The MSL2 RING finger nucleates MSL complex assembly; MLE is only weakly/transiently associated. Yeast two-hybrid, Co-IP, chromatographic co-fractionation, site-directed mutagenesis The EMBO journal High 9736618
1999 SXL inhibits msl-2 splicing by binding the polypyrimidine tract of the regulated intron's 3' splice site, blocking U2AF65 binding and U2 snRNP recruitment. An unusually long distance between the poly(Y) tract and the AG dinucleotide is required. U2AF35 contacts the AG dinucleotide and stabilizes U2AF65 binding, and SXL can only displace U2AF65 when this U2AF35–AG interaction is weak. In vitro splicing assays, UV crosslinking, mutational analysis of splice sites Nature High 10617208
1999 SXL-mediated translational repression of msl-2 mRNA requires cooperation between SXL-binding sites in both the 5' and 3' UTRs and occurs by a poly(A) tail-independent mechanism, as demonstrated in a cell-free Drosophila embryo translation system. Cell-free translation system from Drosophila embryos, mutational analysis of UTRs The EMBO journal High 10545124
2001 SXL inhibits msl-2 5' splice site recognition by binding a uridine-rich sequence downstream of the 5' splice site, preventing TIA-1 binding to that sequence and thereby blocking U1 snRNP recruitment. Combined with 3' splice site inhibition, SXL enforces intron retention via dual-site blockade. Psoralen crosslinking, in vitro splicing assays, UV-crosslinking, mutational analysis RNA High 11565743
2003 SXL inhibits msl-2 mRNA translation initiation by preventing the stable association of the 40S ribosomal subunit with the mRNA; this requires SXL binding to both 5' and 3' UTRs and does not require a cap structure at the 5' end. In vitro translation assays, ribosome association assays (sucrose gradient), mutational analysis Molecular cell High 12769862
2003 SXL acts as a translational repressor through its two RRM domains and a C-terminal heptapeptide extension; its repressor function is activated only when SXL binds msl-2 mRNA via its own RRMs. SXL recruits co-repressor proteins to the msl-2 3' UTR via sequences adjacent to its binding sites, and this requires an intact repressor domain. In vitro translation assays, UV-crosslinking, co-immunoprecipitation, tethering assays The EMBO journal High 14532129
2005 The N-terminal leucine zipper-like motif of MSL1 directly binds MSL2, and the basic motif at the MSL1 N-terminus is required for X chromosome binding. A glycine-rich region mediates MSL1 self-association and association with the MSL complex assembled on the X chromosome. Yeast two-hybrid, in vitro binding, polytene chromosome immunostaining in mutants Molecular and cellular biology High 16199870
2005 MSL2 is stably (essentially immobile) associated with the X chromosome during interphase, as measured by photobleaching (FRAP) in living cells. Knockdown of MSL2 abolishes H4K16 acetylation and the twofold transcriptional elevation of the male X chromosome. Targeting MSL2 to a reporter gene is sufficient to initiate local dosage compensation. FRAP in living cells, RNAi knockdown, reporter gene tethering, transcription assays Chromosoma High 16179989
2006 SXL recruits UNR (upstream of N-ras) to the msl-2 mRNA 3' UTR as a co-repressor; UNR is required for 3' UTR-mediated translational repression of msl-2, and SXL confers a female-specific function to the otherwise ubiquitous UNR protein. mRNP purification (mass spectrometry), co-immunoprecipitation, functional reporter assays, RNAi depletion Genes & development High 16452508
2007 The N-terminal RING finger domain of MSL2, in complex with MSL1, binds to the heterochromatic chromocenter and a few chromosomal arm sites. The carboxyl-terminal domain of MSL2 (proline-rich and basic motifs) is required for binding to hundreds of X-chromosomal sites and for efficient incorporation of roX RNAs into the MSL complex. Incorporation of roX RNAs alters the chromatin-binding specificity of the MSL1/MSL2 complex. GFP-fusion protein localization, domain deletion analysis, polytene chromosome immunostaining Molecular and cellular biology High 18086881
2009 The SXL–UNR co-repressor complex inhibits ribosome recruitment to msl-2 mRNA via a PABP (poly(A)-binding protein)-dependent mechanism: efficient 3' UTR-mediated repression requires a poly(A) tail and PABP function, UNR directly interacts with PABP, and the repressor complex targets ribosome binding after PABP-mediated recruitment of eIF4E/G. In vitro translation assays, ribosome recruitment biochemical assays, protein-protein interaction assays Molecular cell High 19941818
2010 The CXC domain of MSL2 directly binds DNA with low nanomolar affinity in vitro. In vivo, the CXC domain is required for faithful targeting of the dosage compensation complex to the X chromosome; deletion of the CXC domain impairs DCC targeting in reporter assays and GFP-fusion localization experiments. Recombinant protein DNA-binding assay, reporter gene assay in vivo, GFP-fusion localization Nucleic acids research High 20139418
2011 Human MSL2, together with MSL1, functions as a histone E3 ubiquitin ligase that ubiquitylates nucleosomal H2B specifically on lysine 34 (H2B K34ub). H2B K34ub by MSL1/2 directly stimulates H3 K4 and K79 methylation through trans-tail crosstalk in vitro and in cells. This activity is important for transcription activation at HOXA9 and MEIS1 loci and is evolutionarily conserved in Drosophila. In vitro ubiquitylation assay with reconstituted nucleosomes, mass spectrometry (site mapping), co-IP, ChIP, cell-based transcription assays Molecular cell High 21726816
2011 Free (non-chromatin-associated) nuclear MSL complex binds spliced, polyadenylated msl2 mRNA, suggesting a feedback mechanism where excess MSL complex titrates newly transcribed msl2 mRNA to regulate the amount of available MSL complex. RNA immunoprecipitation, ChIP, biochemical fractionation Nucleic acids research Medium 21551218
2012 MSL2 is an E3 ubiquitin ligase that auto-ubiquitylates itself and ubiquitylates other MSL complex components (including MSL1, with sites mapped by mass spectrometry) when their stoichiometry is unbalanced, targeting them for proteasomal degradation. This provides homeostatic control of MSL complex levels. In vitro ubiquitylation assay, mass spectrometry (modification site mapping), proteasome inhibitor experiments, chromatin interaction assays Molecular cell High 23084834
2012 The CXC domain of MSL2 adopts a solution structure with an unusual Zn3Cys9 cluster (three zinc ions coordinated by six terminal and three bridging cysteines), determined by NMR. This domain shows unexpected structural homology to pre-SET motifs of histone lysine methyltransferases. NMR spectroscopy, 1H-113Cd correlation experiments for metal-cysteine connectivity PloS one High 23029009
2013 SXL promotes nuclear retention of msl2 mRNA via a third mechanism (in addition to splicing inhibition and translational repression): SXL recruits the STAR protein HOW to the msl2 5' UTR, and HOW is required for nuclear retention of msl2 transcripts but not for splicing or translational repression. GRAB purification (GST pulldown + RNA affinity), co-immunoprecipitation, reporter assays, RNAi depletion, nuclear fractionation Genes & development High 23788626
2013 hMSL2 functions in the vertebrate DNA damage response: Msl2-/- chicken cells and hMSL2-depleted human cells show defects in non-homologous end joining (NHEJ). hMSL2 is stabilized after DNA damage, and mediates ubiquitylation of 53BP1 at K1690. hMSL1 and hMOF are also modified in the presence of hMSL2 after DNA damage. Gene disruption in DT40 cells, DNA repair assays (NHEJ), immunoblotting, biochemical chromatin analysis, RNAi in human cells PloS one Medium 23874665
2014 The CXC domain of MSL2 specifically recognizes the MRE (MSL recognition element) motif on the X chromosome. Crystal structure of the CXC domain bound to specific and nonspecific DNAs shows the domain contacts one strand of the DNA duplex and uses a single arginine to read out dinucleotide sequences from the minor groove. The MRE core harbors two binding sites on opposite strands that cooperatively recruit a CXC dimer. Specific DNA-binding mutants are impaired in MRE binding and X chromosome localization in vivo. Crystal structure determination, in vitro DNA-binding assays, mutagenesis, in vivo localization Genes & development High 25452275
2017 Human MSL2 maintains HBV covalently closed circular DNA (cccDNA) stability by ubiquitylating and degrading APOBEC3B in hepatoma cells. HBV X protein (HBx) upregulates MSL2 expression through activation of YAP/FoxA1 signaling acting on the MSL2 promoter. Co-IP/ubiquitylation assays, siRNA knockdown, luciferase reporter assays, ChIP, xenograft tumor assays Hepatology Medium 28608964
2018 Hrp48 is a SXL co-factor that binds the 3' UTR of msl-2 and is required for optimal translational repression by SXL. Hrp48 interacts with eIF3d, a subunit of the eIF3 translation initiation complex; eIF3d binds the msl-2 5' UTR and is required for efficient translation and translational repression of msl-2. eIF3d depletion (but not other eIF3 subunits) de-represses msl-2 in female flies, consistent with Hrp48 inhibiting translation by targeting eIF3d. Co-IP, RNA chromatography, reporter assays, RNAi in cells and in vivo Nucleic acids research High 29635389
2019 MSL2 ubiquitylation of H2B depends on substrate configuration: MSL1/2 efficiently ubiquitylates free histone substrates but very poorly modifies intact nucleosomes, implying a requirement for nucleosomal structural alteration for efficient H2B K34 ubiquitylation in vivo. MSL1/2 can deposit two ubiquitin moieties per nucleosome. In vitro ubiquitylation assays with purified MSL1/MSL2, nucleosome gel-mobility shift assay, various histone substrates Archives of biochemistry and biophysics Medium 30930284
2019 MSL2 interacts directly with CLAMP through a conserved domain (CBD, clamp-binding domain) in MSL2 and the N-terminal zinc-finger domain of CLAMP. Inactivation of either the CBD or CXC domain individually only modestly affects DCC recruitment to the X chromosome, but combining both lesions in the same MSL2 mutant causes markedly increased loss of DCC recruitment, demonstrating redundancy between CLAMP-interaction and DNA-binding for DCC targeting. Genetic epistasis (double mutant), in vivo DCC localization assays, two-hybrid/binding assays Development High 31320325
2020 The low-complexity C-terminal domain (CTD) of MSL2 and roX non-coding RNAs form a stably condensed compartment that is the primary determinant for X chromosome-specific compartmentalization in Drosophila. Replacing the CTD of mammalian MSL2 with that from Drosophila and expressing roX in cis is sufficient to nucleate ectopic dosage compensation in mammalian cells, demonstrating that roX RNA nucleation by the MSL2 CTD drives X chromosome compartmentalization. In vivo functional assays in Drosophila and mammalian cells, domain-swap experiments, condensate/phase separation assays Nature High 33208948
2022 The intrinsically disordered region of MSL2 directly interacts with the N-terminal C2H2 zinc-finger domain of CLAMP. NMR structure of the CLAMP N-terminal C2H2 zinc finger reveals a classic fold with an unusual distribution of DNA-recognition residues. The MSL2 interaction region is conserved only within Drosophila, indicating this interaction evolved specifically for DCC recruitment. NMR structure determination, interaction mapping, mutagenesis, viability assays Nucleic acids research High 35648444
2023 Cooperative binding of MSL2 and CLAMP to MRE (MSL recognition element) sites requires direct physical interaction between the two proteins; disruption of this interaction converts cooperativity to competition at composite binding sites. Cooperativity occurs largely at individual MRE level and is not influenced by MRE clustering or arrangement. Reconstituted chromatin binding assays, mutational analysis of protein-protein interface, CUT&RUN Nucleic acids research High 37602401
2024 The B-domain of MSL2 destabilizes the MSL2 protein through ubiquitylation of two lysines controlled by its own RING domain. The unstructured proline-rich P-domain stimulates transcription of the roX2 gene, which is necessary for effective formation of the dosage compensation complex. Domain deletion analysis, protein stability assays, roX2 transcription reporter assays Biochemistry. Biokhimiia Medium 38831503
2024 Hrp48 binds a specific sequence in the msl-2 3' UTR independently of SXL and UNR, downstream of their binding sites. NMR spectroscopy and ITC defined the exact Hrp48-binding region. Hrp48 further stabilizes RNA-bound SXL indirectly via ATP-independent RNA remodeling. NMR spectroscopy, isothermal titration calorimetry, molecular dynamics simulations, translation assays Biophysical chemistry High 39504588
2025 Single-molecule fluorescence microscopy of msl-2 mRNP assembly showed: SXL targets msl-2 mRNA via sliding and double-binding; Unr recruitment is accelerated >500-fold by RNA-bound SXL; Hrp48 stabilizes RNA-bound SXL indirectly via ATP-independent RNA remodeling, synergistically achieving tight translational repression. Multi-color single-molecule fluorescence microscopy, real-time mRNP assembly tracking bioRxivpreprint Medium bio_10.1101_2025.04.07.647595

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Expression of msl-2 causes assembly of dosage compensation regulators on the X chromosomes and female lethality in Drosophila. Cell 273 7781064
1999 Inhibition of msl-2 splicing by Sex-lethal reveals interaction between U2AF35 and the 3' splice site AG. Nature 247 10617208
1997 The regulation of the Drosophila msl-2 gene reveals a function for Sex-lethal in translational control. Cell 177 9182767
1995 The msl-2 dosage compensation gene of Drosophila encodes a putative DNA-binding protein whose expression is sex specifically regulated by Sex-lethal. Development (Cambridge, England) 144 7588059
2011 The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3 K4 and K79 methylation. Molecular cell 132 21726816
1999 Translational control of dosage compensation in Drosophila by Sex-lethal: cooperative silencing via the 5' and 3' UTRs of msl-2 mRNA is independent of the poly(A) tail. The EMBO journal 115 10545124
1998 Complex formation by the Drosophila MSL proteins: role of the MSL2 RING finger in protein complex assembly. The EMBO journal 106 9736618
2006 Sex-lethal imparts a sex-specific function to UNR by recruiting it to the msl-2 mRNA 3' UTR: translational repression for dosage compensation. Genes & development 76 16452508
2017 Hepatitis B virus X protein-elevated MSL2 modulates hepatitis B virus covalently closed circular DNA by inducing degradation of APOBEC3B to enhance hepatocarcinogenesis. Hepatology (Baltimore, Md.) 64 28608964
1995 The dosage compensation regulators MLE, MSL-1 and MSL-2 are interdependent since early embryogenesis in Drosophila. Mechanisms of development 64 8562424
2009 The SXL-UNR corepressor complex uses a PABP-mediated mechanism to inhibit ribosome recruitment to msl-2 mRNA. Molecular cell 62 19941818
2003 Drosophila sex-lethal inhibits the stable association of the 40S ribosomal subunit with msl-2 mRNA. Molecular cell 60 12769862
2010 The DNA binding CXC domain of MSL2 is required for faithful targeting the Dosage Compensation Complex to the X chromosome. Nucleic acids research 59 20139418
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
2003 A co-repressor assembly nucleated by Sex-lethal in the 3'UTR mediates translational control of Drosophila msl-2 mRNA. The EMBO journal 44 14532129
2020 RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature 39 33208948
2005 Stable chromosomal association of MSL2 defines a dosage-compensated nuclear compartment. Chromosoma 33 16179989
2018 The long noncoding RNA MALAT-1 functions as a competing endogenous RNA to regulate MSL2 expression by sponging miR-338-3p in myasthenia gravis. Journal of cellular biochemistry 29 30362606
2012 MSL2 combines sensor and effector functions in homeostatic control of the Drosophila dosage compensation machinery. Molecular cell 29 23084834
2001 Modulation of msl-2 5' splice site recognition by Sex-lethal. RNA (New York, N.Y.) 29 11565743
2014 Structural basis of X chromosome DNA recognition by the MSL2 CXC domain during Drosophila dosage compensation. Genes & development 26 25452275
1982 Studies on the sex-specific lethals of Drosophila melanogaster. V. Sex transformation caused by interactions between a female-specific lethal, Sxlf 1, and the male-specific lethals mle(3)132, msl-2(27), and mle. Genetics 20 6818105
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
2013 Sex-lethal promotes nuclear retention of msl2 mRNA via interactions with the STAR protein HOW. Genes & development 19 23788626
2018 Hrp48 and eIF3d contribute to msl-2 mRNA translational repression. Nucleic acids research 18 29635389
2012 Solution structure of MSL2 CXC domain reveals an unusual Zn3Cys9 cluster and similarity to pre-SET domains of histone lysine methyltransferases. PloS one 18 23029009
1982 Studies on the sex-specific lethals of Drosophila melanogaster. IV. Gynandromorph analysis of three male-specific lethals, mle, msl-2(27) and mle(3)132. Genetics 18 6818104
2011 msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster. Nucleic acids research 17 21551218
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
2019 The simultaneous interaction of MSL2 with CLAMP and DNA provides redundancy in the initiation of dosage compensation in Drosophila males. Development (Cambridge, England) 15 31320325
2022 Structural basis for interaction between CLAMP and MSL2 proteins involved in the specific recruitment of the dosage compensation complex in Drosophila. Nucleic acids research 10 35648444
2020 IFN-α2b inhibits the ethanol enriched-HBV cccDNA through blocking a positive feedback loop of HBx/MSL2/cccDNA/HBV/HBx in liver. Biochemical and biophysical research communications 9 32446394
2024 MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature. American journal of human genetics 8 38815585
2019 Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis. Oncology letters 8 31612010
2023 Physical interaction between MSL2 and CLAMP assures direct cooperativity and prevents competition at composite binding sites. Nucleic acids research 7 37602401
2015 X-to-autosome expression and msl-2 transcript abundance correlate among Drosophila melanogaster somatic tissues. PeerJ 6 25737812
2013 Msl2 is a novel component of the vertebrate DNA damage response. PloS one 6 23874665
2024 The Drosophila RNA binding protein Hrp48 binds a specific RNA sequence of the msl-2 mRNA 3' UTR to regulate translation. Biophysical chemistry 5 39504588
2024 Novel protein-truncating variants of a chromatin-modifying gene MSL2 in syndromic neurodevelopmental disorders. European journal of human genetics : EJHG 4 38702431
2021 In Hepatocellular Carcinoma, miRNA-296-3p Targets MSL2 and Suppresses Cell Proliferation and Invasion. Journal of oncology 4 34899909
2019 Analysis of histone ubiquitylation by MSL1/MSL2 proteins in vitro. Archives of biochemistry and biophysics 4 30930284
2025 Prenatal Diagnosis of MSL2-Related Ventriculomegaly in Association With an Inherited 15q13 Microduplication. Clinical genetics 1 40954079
2024 Functional Role of C-terminal Domains in the MSL2 Protein of Drosophila melanogaster. Biochemistry. Biokhimiia 1 38831503