Centro 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
Sonia Barroso
Centro 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
Nibal Badra-Fajardo
Centro 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
José Javier Marqueta-Gracia
Centro 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
María L. García-Rubio
Centro 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
Patricia Ubieto-Capella
Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
Juan Méndez
Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain
Andrés Aguilera
Centro 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; Corresponding author
Summary: During genome duplication, replication forks (RFs) can be stalled by different obstacles or by depletion of replication factors or nucleotides. A limited number of histone post-translational modifications at stalled RFs are involved in RF protection and restart. Provided the recent observation that the SIN3A histone deacetylase complex reduces transcription-replication conflicts, we explore the role of the SIN3A complex in protecting RFs under stressed conditions. We observe that Sin3A protein is enriched at replicating DNA in the presence of hydroxyurea. In this situation, Sin3A-depleted cells show increased RF stalling, H3 acetylation, and DNA breaks at stalled RFs. Under Sin3A depletion, RF recovery is impaired, and DNA damage accumulates. Importantly, these effects are partially dependent on the MUS81 endonuclease, which promotes DNA breaks and MRE11-dependent DNA degradation of such breaks. We propose that chromatin deacetylation triggered by the SIN3A complex limits MUS81 cleavage of stalled RFs, promoting genome stability when DNA replication is challenged.
