title: MDC1 cleavage by caspase-3: a novel mechanism for inactivating the DNA damage response during apoptosis.
abstract: Recently, we identified the "apoptotic ring," containing phosphorylated histone H2AX (γ-H2AX), as an early chromatin modification during apoptosis. Because γ-H2AX initiates the DNA damage response (DDR), we tested whether the apoptotic H2AX response leads to the full recruitment of the DDR factors that normally coordinate DNA repair and cell-cycle checkpoints. We show that the apoptotic H2AX response does not recruit the DDR factors because MDC1 (mediator of DNA damage checkpoint protein 1), which normally binds to γ-H2AX in response to DNA damage and amplifies the DDR, is cleaved by caspase-3. This cleavage separates the BRCT and FHA domains of MDC1 and constitutes a novel mechanism for the inactivation of DNA repair in apoptotic cells. Also, we show that downregulation of MDC1 increases the apoptotic response to TRAIL. Together, these results implicate MDC1 in the cellular apoptotic response.
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Solier
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004249:DNA Damage; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1; D053148:Caspase 3