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SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability

Sergio Muñoz1, Sonia Barroso1, Nibal Badra-Fajardo1

  • 1Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, 41092 Seville, Spain; Departamento de Genética, Facultad de Biología, Universidad de Sevilla, 41012 Seville, Spain.

Cell Reports
|February 11, 2024
PubMed

Insights

The SIN3A complex protects genome stability by deacetylating histones at stalled replication forks (RFs), preventing DNA breaks and promoting replication restart under stress.

Area of Science:

  • Molecular Biology
  • Genetics
  • Epigenetics

Background:

  • Replication forks (RFs) can stall due to obstacles or depleted resources during DNA replication.
  • Histone modifications play a role in protecting and restarting stalled RFs.
  • The SIN3A histone deacetylase complex is known to resolve transcription-replication conflicts.

Purpose of the Study:

  • To investigate the role of the SIN3A complex in protecting RFs under stressed conditions.
  • To determine how SIN3A influences histone modifications and DNA breaks at stalled RFs.

Main Methods:

  • Observed Sin3A protein enrichment at replicating DNA during hydroxyurea treatment.
  • Analyzed RF stalling, H3 acetylation, and DNA breaks in Sin3A-depleted cells.
  • Assessed RF recovery and DNA damage accumulation under Sin3A depletion.
  • Investigated the dependence on MUS81 endonuclease and MRE11-dependent DNA degradation.

Main Results:

  • Sin3A protein is enriched at replicating DNA under hydroxyurea stress.
  • Sin3A depletion leads to increased RF stalling, H3 acetylation, and DNA breaks.
  • RF recovery is impaired and DNA damage accumulates in Sin3A-depleted cells.
  • These effects are partially dependent on MUS81 endonuclease activity.

Conclusions:

  • The SIN3A complex limits MUS81 cleavage of stalled RFs through chromatin deacetylation.
  • SIN3A promotes genome stability during challenged DNA replication.
  • SIN3A's role in deacetylation is crucial for preventing DNA breaks and ensuring replication restart.
Keywords:
CP: Molecular biologyMUS81SIN3A complexhistone deacetylationreplication forkreplication stress

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