Nucleolar accumulation of APE1 depends on charged Lysine residues that undergo acetylation upon genotoxic stress and modulate its BER activity in cells.

APE1 is the main abasic endonuclease in the BER pathway of DNA lesions caused by oxidation/alkylation in mammalian cells; within nucleoli it interacts with Nucleophosmin and rRNA through N-terminal Lys residues, some of which (K(27)/K(31)/K(32)/K(35)) may undergo acetylation in vivo. Here, we studied the functional role of these modifications during genotoxic damage and their in vivo relevance. We demonstrated that cells expressing a specific K to A multiple mutant are APE1 nucleolar-deficient and are more resistant to genotoxic treatment than those expressing the wild type one, although they showed impaired proliferation. Interestingly, we found that genotoxic treatment induces acetylation at these K residues. We also found that the charged status of K(27)/K(31)/K(32)/K(35) modulates acetylation at K(6)/K(7) residues which are known to be involved in the coordination of BER activity, through a mechanism regulated by the SIRT1 deacetylase. Notably, structural studies showed that acetylation at K(27)/K(31)/K(32)/K(35) may account for local conformational changes on APE1 protein structure. These results highlight the emerging role of acetylation of critical Lys residues in regulating APE1 functions. They also suggest the existence of cross-talk between different Lys residues of APE1, occurring upon genotoxic damage, which may modulate APE1 subnuclear distribution and enzymatic activity in vivo.