Distinct DAXX effector modules separate H3.3 nucleosome assembly from ERV silencing.
Biorxiv : the Preprint Server for Biology
|March 25, 2026
Summary
Endogenous retroviruses (ERVs) are silenced by the protein DAXX. While DAXX’s histone-binding domain is crucial for recruiting H3.3, this histone is not required for silencing ERVs, with SUMO-dependent recruitment being key.
Area of Science:
- Molecular Biology
- Epigenetics
- Genomics
Background:
- Endogenous retroviruses (ERVs) can disrupt genome integrity when active.
- Cells utilize chromatin-based mechanisms to suppress ERV transcription.
- The histone chaperone DAXX is known to silence a subset of ERVs via unclear pathways.
Purpose of the Study:
- To elucidate the mechanisms by which DAXX silences endogenous retroviruses.
- To determine the roles of DAXX's histone-binding domain and SUMO-interacting motif in ERV silencing.
Main Methods:
- Biochemical assays to study DAXX-DNA and DAXX-histone interactions.
- Genetic manipulation in cells to assess DAXX function at ERVs.
- Analysis of H3.3 deposition and SUMOylated repressor recruitment.
Main Results:
- A conserved basic patch in DAXX's histone-binding domain interacts with DNA and facilitates H3.3 nucleosome assembly in vitro.
- This basic patch is necessary for H3.3 enrichment at ERVs but dispensable for DAXX-mediated ERV silencing.
- DAXX-mediated ERV silencing critically depends on its C-terminal SUMO-interacting motif for recruiting repressors like MORC3.
Conclusions:
- DAXX-mediated ERV silencing is uncoupled from H3.3 nucleosome deposition.
- SUMO-dependent recruitment of effector proteins, such as MORC3, is the primary mechanism for DAXX-mediated ERV silencing.
- DAXX functions through modular outputs, separating histone chaperone activity from direct silencing functions.
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