Structural mechanisms underlying signaling in the cellular response to DNA double strand breaks

• Double strand break (DSB) signaling is initiated with lesion recognition by MRN.
• DSB recognition leads to protein kinase activation and H2AX phosphorylation.
• DSB-linked phosphorylation is specifically recognized by BRCT and FHA domain proteins.
• Phosphorylation leads to modification of chromatin by Lys63-linked polyubiquitin.
• Lys63-linked polyubiquitin is recognized by RAP80 tUIM and recruitment of BRCA1.

DNA double strand breaks (DSBs) constitute one of the most dangerous forms of DNA damage. In actively replicating cells, these breaks are first recognized by specialized proteins that initiate a signal transduction cascade that modulates the cell cycle and results in the repair of the breaks by homologous recombination (HR). Protein signaling in response to double strand breaks involves phosphorylation and ubiquitination of chromatin and a variety of associated proteins. Here we review the emerging structural principles that underlie how post-translational protein modifications control protein signaling that emanates from these DNA lesions.