The Participation of myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, in DNA repair and homologous recombination (HR) is not well understood. This study tests whether MCL-1 interacts with Males absent On First (MOF) to regulate H4K16 acetylation that promotes HR repair in response to replication stress induced by Hydroxyurea (HU) treatment. Co-immunoprecipitation of FLAG-MCL-1 from cancer cells treated with HU pulls down a complex of MCL-1, MOF and BH3-interacting domain death agonist (BID). The same complex is pulled down in cells treated with HU that express FLAG-MOF. MCL-1 regulates H4K16 acetylation during HU-induced replication stress since knockdown of MCL-1 decreases H4K16 acetylation while re-expression of MCL-1 restores H4K16 acetylation. Furthermore, knockdown of BID rescues the clonogenic survival in MCL-1 depleted cells in response to replication stress which is associated with decreased Caspase 3/7 activity compared to MCL-1 depleted cells. Cells depleted in both MCL-1 and BID display increased HR repair efficiency by direct repeats-green fluorescent protein assay and in response to HU exhibit increased ATR, Chk1, and RPA phosphorylation relative to MCL-1 depleted cells. This study uncovers that MCL-1 cooperates with MOF and regulates HR repair through H4K16 acetylation. Further, this study determines that MCL-1 and BID cooperate to regulate the crosstalk between HR repair and apoptosis.
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