Formation of Dynamic γ-H2AX Domains along Broken DNA Strands Is Distinctly Regulated by ATM and MDC1 and Dependent upon H2AX Densities in Chromatin

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. Bassing

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)298-310
Number of pages13
JournalMolecular cell
Volume34
Issue number3
DOIs
StatePublished - May 15 2009

Keywords

  • DNA

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