TOR complex 2 is required for histone H2A phosphorylation in response to DNA damage and under long-term quiescence

The target of rapamycin (TOR) protein kinase is a key regulator of cellular growth, proliferation and survival that can be found in two distinct multi-subunit complexes, TOR complex 1 and 2 (TORC1 and TORC2). Intriguingly, fission yeast TOR complex 2 (TORC2) is required for cell survival under DNA damaging conditions. This is dependent on the only known direct target of TORC2, Gad8 (AKT or SGK1 in human cells). Perturbation of TORC2-Gad8 signaling results in severe sensitivity to DNA damaging conditions, an accumulation of homologous recombination (HR)-Rad52 repair foci and dependency on HR for cell viability. However, TORC2-Gad8 is dispensable for cell cycle delay in response to DNA damage. Upon DNA damage, the Tel1 (ATM) and Rad3 (ATR) checkpoint kinases phosphorylate histone H2A proteins at serine-129 (known as gH2A, equivalent to gH2AX in higher eukaryotes). This type of chromatin modification is required for efficient repair of DNA damage. Here we show Tel1 (ATM)-dependent phosphorylation of Gad8 in long-term quiescent cells, in a process that is independent of TORC2 and is concomitant with the appearance of Tel1-dependent gH2A. Thus, during long-term quiescence, Tel1 becomes active and may engage Gad8 in preserving genome integrity. Moreover, we have found that TORC2-Gad8 is required for generating gH2A in quiescent cells and in non-quiescent growing cells exposed to DNA damaging agents. These results put TORC2-Gad8 in the center of genome stability. Since TORC2-Gad8 is conserved in mammalian cells these results may be relevant for the function of TORC2 in cancer.