Proposed model. SIRT6 binds DNA damage sites, recruits and blocks MAPK signaling, including RSK2. As a result, Chk1 is phosphorylated at Ser317 and maintains genome integrity by repairing DNA injuries. In contrast, inhibiting SIRT6 activity results in hyperactivation of MEK/ERK signaling (by H3K9 acetylation and ELK1-mediated activity), which in turn results in RSK2-mediated Chk1 blockade (which is phosphorylated at Ser280) and ATR/CHK1 signaling impairment. In such a scenario of SIRT6 depletion, G2 DNA damage checkpoint impairment results in enhanced lethality of genotoxic stress.