Journal
MOLECULAR CELL
Volume 34, Issue 3, Pages 298-310Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2009.04.012
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Funding
- Cancer Research Institute
- Training Program in Immune System Development
- National Institutes of Health [R01 A1074953, R01 CA125195]
- Department of Pathology
- Center for Childhood Cancer Research of the Children's Hospital of Philadelphia
- Abramson Family Cancer Research Institute
- Pew Scholar in the Biomedical Sciences Award
- Pennsylvania Department of Health
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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.
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