TY - JOUR
T1 - Formation of Dynamic γ-H2AX Domains along Broken DNA Strands Is Distinctly Regulated by ATM and MDC1 and Dependent upon H2AX Densities in Chromatin
AU - Savic, Velibor
AU - Yin, Bu
AU - Maas, Nancy L.
AU - Bredemeyer, Andrea L.
AU - Carpenter, Andrea C.
AU - Helmink, Beth A.
AU - Yang-Iott, Katherine S.
AU - Sleckman, Barry P.
AU - Bassing, Craig H.
N1 - Funding Information:
We thank Steve Reiner, Thomas Curran, and Celeste Simon for helpful discussions of the manuscript. This work was supported by the Cancer Research Institute Training Grant (V.S. and B.Y.); the Training Program in Immune System Development (A.C.C.); the National Institutes of Health Grant R01 AI074953 (B.P.S.); and the Department of Pathology and the Center for Childhood Cancer Research of the Children's Hospital of Philadelphia, the Abramson Family Cancer Research Institute, a Pew Scholar in the Biomedical Sciences Award, a grant from the Pennsylvania Department of Health, and the National Institutes of Health Grant R01 CA125195 (C.H.B.).
PY - 2009/5/15
Y1 - 2009/5/15
N2 - A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate γ-H2AX. Here, we demonstrate that γ-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which γ-H2AX forms does not spread as DSBs persist; rather, γ-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate γ-H2AX, only ATM promotes γ-H2AX formation to maximal distance and maintains γ-H2AX densities. MDC1 is essential for γ-H2AX formation at high densities near DSBs, but not for generation of γ-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of γ-H2AX formed. Our data suggest that H2AX fuels a γ-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
AB - A hallmark of the cellular response to DNA double-strand breaks (DSBs) is histone H2AX phosphorylation in chromatin to generate γ-H2AX. Here, we demonstrate that γ-H2AX densities increase transiently along DNA strands as they are broken and repaired in G1 phase cells. The region across which γ-H2AX forms does not spread as DSBs persist; rather, γ-H2AX densities equilibrate at distinct levels within a fixed distance from DNA ends. Although both ATM and DNA-PKcs generate γ-H2AX, only ATM promotes γ-H2AX formation to maximal distance and maintains γ-H2AX densities. MDC1 is essential for γ-H2AX formation at high densities near DSBs, but not for generation of γ-H2AX over distal sequences. Reduced H2AX levels in chromatin impair the density, but not the distance, of γ-H2AX formed. Our data suggest that H2AX fuels a γ-H2AX self-reinforcing mechanism that retains MDC1 and activated ATM in chromatin near DSBs and promotes continued local phosphorylation of H2AX.
KW - DNA
UR - https://www.scopus.com/pages/publications/65549129613
U2 - 10.1016/j.molcel.2009.04.012
DO - 10.1016/j.molcel.2009.04.012
M3 - Article
C2 - 19450528
AN - SCOPUS:65549129613
SN - 1097-2765
VL - 34
SP - 298
EP - 310
JO - Molecular cell
JF - Molecular cell
IS - 3
ER -