Article
SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability
Author/s | Muñoz, Sergio
Barroso, Sonia Badra Fajardo, Nibal Marqueta Gracia, José Javier García Rubio, María Luisa Ubieto-Capella, Patricia Méndez, Juan Aguilera López, Andrés |
Department | Universidad de Sevilla. Departamento de Genética |
Publication Date | 2024 |
Deposit Date | 2024-05-31 |
Published in |
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Abstract | 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 ... 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. |
Funding agencies | European Research Council (ERC) Ministerio de Ciencia e Innovación (MICIN). España Agencia Estatal de Investigación. España Fundación de Investigación de la Universidad de Sevilla Foundation "Vencer el Cancer" European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) |
Project ID. | ERC2014 AdG669898 TARLOOP
PID2019-104270GB-I00/BMC FIUS22/01788 PID2019-106707-RB |
Citation | Muñoz, S., Barroso, S., Badra Fajardo, N., Marqueta Gracia, J.J., García Rubio, M.L., Ubieto-Capella, P.,...,Aguilera López, A. (2024). SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability. Cell Reports, 43 (2), 113778. https://doi.org/10.1016/j.celrep.2024.113778. |
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