Abstract
Phosphorylation of KAT5 by ABL upon chromatin perturbation or DNA damage enhances ATM activity.
Major finding: Phosphorylation of KAT5 by ABL upon chromatin perturbation or DNA damage enhances ATM activity.
Clinical relevance: ABL inhibition may augment the effects of DNA damaging agents or epigenetic therapies.
Impact: KAT phosphorylation serves as a sensing mechanism linking chromatin to the DNA damage response.
DNA double-strand breaks (DSB) induce changes in chromatin structure, but the mechanisms linking chromatin alterations to the DNA damage response are poorly understood. Lysine acetyltransferase 5 (KAT5, also known as TIP60) binds trimethylated histone H3 lysine 9 (H3K9me3) and acetylates ATM, which promotes ATM phosphorylation and activation of the DNA damage response, but it is unknown how KAT5 binding is regulated. Kaidi and Jackson found that binding of KAT5 to H3K9me3 increased in response to ionizing radiation and was dependent on tyrosine phosphorylation of the KAT5 chromodomain. KAT5 phosphorylation was not required for its histone acetyltransferase activity but was necessary for acetylation of ATM, phosphorylation of downstream ATM targets, and activation of DNA damage–induced cell-cycle checkpoints, indicating that KAT5 has distinct roles in regulating gene expression and the DNA damage response. Interestingly, alterations in chromatin structure induced by histone deacetylase inhibition or heterochromatin protein 1α depletion also facilitated KAT5 binding to H3K9me3 and induced KAT5 phosphorylation and ATM acetylation, indicating that chromatin perturbations can also activate ATM signaling in the absence of DNA damage. Increased binding to H3K9me3 protected KAT5 from phosphatase activity and enhanced accumulation of phosphorylated KAT5, revealing a mechanism coupling changes in chromatin structure to activation of checkpoint signaling. Consistent with previous studies indicating that the tyrosine kinase ABL plays a role in ATM activation, ABL directly phosphorylated KAT5 in vitro and was required for accumulation of phosphorylated KAT5, ATM signaling, and cell-cycle checkpoint activation after ionizing radiation or histone deacetylase inhibitor treatment. Together, these findings indicate that KAT5 phosphorylation links changes in chromatin structure to ATM-mediated checkpoint signaling and raises the possibility that clinically available ABL inhibitors may disrupt the DNA damage response and potentiate the effects of DSB-inducing chemotherapeutic agents or chromatin modulators.