Abstract 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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