γH2AX and MDC1: Anchoring the DNA-damage-response machinery to broken chromosomes

Higher-order chromatin structure presents a barrier to the recognition and repair of DNA lesions. Thus, cells must be equipped with mechanisms to surpass this natural obstacle. DNA damage induces histone H2AX phosphorylation by the phosphoinositide 3-kinase like kinases ATM, ATR and DNA-PKcs. H2AX phosphorylation contributes to DNA double-strand break repair but the mechanisms involved are not yet fully understood. In this review, we discuss recent advances in our understanding of how cells use the epigenetic mark of H2AX phosphorylation to dynamically link the DNA-damage-response machinery to broken chromosomes. In addition, we highlight potential regulatory mechanisms of H2AX phosphorylation and speculate about a central functional role of this post-translational histone modification at the interface of DNA repair, chromatin-structure modulation and cell-cycle checkpoint activation.