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APLF is a forkhead associated (FHA) domain-containing protein with unique poly(ADP)-ribose (PAR)-binding zinc finger (PBZ) domains that are involved in the DNA damage response. The interaction of the APLF PBZ domains with PAR is essential for the rapid recruitment of APLF to sites of DNA double strand breaks (DSBs), while the FHA domain facilitates non-homologous end-joining. In response to ionizing radiation (IR), APLF is phosphorylated at Serine-116 (APLFS116), although the function of this post-translational modification has yet to be defined. Here we provide a detailed characterization of the IR-induced and ATM- dependent phosphorylation of endogenous APLF at Serine-116 in the context of DNA damage. We additionally examine a novel APLF FHA-dependent interaction with 53BP1 (p53 Binding protein 1). Together, we illustrate that APLFS116 phosphorylation is dependent upon both the tandem PBZ domains, as well as the FHA-domain, and that the depletion of either PARP3 or 53BP1, similarly affected APLFS116 phosphorylation. Furthermore, we show that DSB-repair was compromised in cells expressing the APLFS116A mutation. Collectively, our findings provide a detailed understanding of the molecular pathway that leads to the phosphorylation of APLF following DNA damage and suggest that APLFS116 phosphorylation facilitates APLF-dependent DSB repair.

APLF is a forkhead associated (FHA) domain-containing protein with unique poly(ADP)-ribose (PAR)-binding zinc finger (PBZ) domains that are involved in the DNA damage response. The interaction of the APLF PBZ domains with PAR is essential for the rapid recruitment of APLF to sites of DNA double strand breaks (DSBs), while the FHA domain facilitates non-homologous end-joining. In response to ionizing radiation (IR), APLF is phosphorylated at Serine-116 (APLFS116), although the function of this post-translational modification has yet to be defined. Here we provide a detailed characterization of the IR-induced and ATM- dependent phosphorylation of endogenous APLF at Serine-116 in the context of DNA damage. We additionally examine a novel APLF FHA-dependent interaction with 53BP1 (p53 Binding protein 1). Together, we illustrate that APLFS116 phosphorylation is dependent upon both the tandem PBZ domains, as well as the FHA-domain, and that the depletion of either PARP3 or 53BP1, similarly affected APLFS116 phosphorylation. Furthermore, we show that DSB-repair was compromised in cells expressing the APLFS116A mutation. Collectively, our findings provide a detailed understanding of the molecular pathway that leads to the phosphorylation of APLF following DNA damage and suggest that APLFS116 phosphorylation facilitates APLF-dependent DSB repair.

The reaction of polycyclic hydrocarbon epoxides with the phosphate group of DNA has been suggested as potentially important in the cancer process initiated by this class of compounds. Herein the chemical reactions of model phosphates with various classes of epoxides are investigated. With aliphatic and non-bay-region type expoxides the reaction occurred by stereospecific trans addition of phosphate on the epoxide. Various physical-chemical aspects of this reaction are investigated. With K-region type epoxides the same reaction gave exclusively phenols. The biological implications of this result are discussed. Finally, bay-region type oxides, on reaction with phosphate, gave phosphotriesters whose stabilities depend on the phosphodiester nucleophile used and on the presence and arrangement of the diol grouping next to the epoxide.