MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres.
Here we document the role of MDC1 (mediator of DNA damage checkpoint 1) in the detection and repair of human and mouse telomeres rendered dysfunctional through inhibition of TRF2. Consistent with its role in promoting DNA damage foci, MDC1 knockdown affected the formation of telomere dysfunction-induced foci (TIFs), diminishing the accumulation of phosphorylated ATM, 53BP1, Nbs1, and to a lesser extent, gamma-H2AX. In addition to this effect on TIFs, the rate of nonhomologous end-joining (NHEJ) of dysfunctional telomeres was significantly decreased when MDC1 itself or its recruitment to chromatin was inhibited. MDC1 appeared to promote a step in the NHEJ pathway after the removal of the 3' telomeric overhang. The acceleration of NHEJ was unlikely to be due to increased presence of 53BP1 and Mre11 in TIFs, since knockdown of neither factor affected telomere fusions. Furthermore, relevant cell cycle effectors (Chk2, p53, and p21) of the ATM kinase pathway were unaffected and there was no change in the rate of cell cycle progression. We propose that the binding of MDC1 to gamma-H2AX directly affects NHEJ in a manner that is independent of the ATM-dependent cell cycle arrest pathway.
Dimitrova
Nadya
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Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10021, USA.
de Lange
Titia
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D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D035182:TATA Box Binding Protein-Like Proteins / Q000172:deficiency; D016615:Telomere / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2 / Q000172:deficiency; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; C508937:MDC1 protein, mouse; D009687:Nuclear Proteins; D035182:TATA Box Binding Protein-Like Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D015534:Trans-Activators