Formation of Dynamic γ-H2AX Domains along Broken DNA Strands Is Distinctly Regulated by ATM and MDC1 and Dependent upon H2AX Densities in Chromatin
Copyright policy )Formation of Dynamic γ-H2AX Domains along Broken DNA Strands Is Distinctly Regulated by ATM and MDC1 and Dependent upon H2AX Densities in Chromatin
A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate gamma-H2AX. Here, we demonstrate that gamma-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which gamma-H2AX forms does not spread as DSBs persist; rather, gamma-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate gamma-H2AX, only ATM promotes gamma-H2AX formation to maximal distance and maintains gamma-H2AX densities. MDC1 is essential for gamma-H2AX formation at high densities near DSBs, but not for generation of gamma-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of gamma-H2AX formed. Our data suggest that H2AX fuels a gamma-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
- University of Pennsylvania United States
- Children's Hospital of Philadelphia United States
- Washington University in St. Louis United States
- Abramson Cancer Center United States
- University of Mary United States
Mice, Knockout, Recombination, Genetic, B-Lymphocytes, G1 Phase, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Cell Cycle Proteins, Cell Biology, Ataxia Telangiectasia Mutated Proteins, DNA, Thymus Gland, Protein Serine-Threonine Kinases, Endonucleases, Chromatin, DNA-Binding Proteins, Histones, Mice, Animals, Molecular Biology, Genes, T-Cell Receptor alpha, Adaptor Proteins, Signal Transducing, DNA Damage
Mice, Knockout, Recombination, Genetic, B-Lymphocytes, G1 Phase, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Cell Cycle Proteins, Cell Biology, Ataxia Telangiectasia Mutated Proteins, DNA, Thymus Gland, Protein Serine-Threonine Kinases, Endonucleases, Chromatin, DNA-Binding Proteins, Histones, Mice, Animals, Molecular Biology, Genes, T-Cell Receptor alpha, Adaptor Proteins, Signal Transducing, DNA Damage
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