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Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin
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posted on 2023-06-08, 14:17 authored by Velibor Savic, Bu Yin, Nancy L Maas, Andrea L Bredemeyer, Andrea C Carpenter, Beth A Helmink, Katherine S Yang-Iott, Barry P Sleckman, Craig H BassingA 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
History
Publication status
- Published
Journal
Molecular CellISSN
1097-2765Publisher
ElsevierExternal DOI
Issue
3Volume
34Page range
298-310Department affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2013-02-11Usage metrics
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