Figure 7

Proposed model for the interplay between HIPK2 and SIRT1 at PML-NBs upon severe genotoxic stress. Our data propose that in response to severe DNA damage SIRT1 and HIPK2 are recruited to PML-NBs by the PML isoform IV. Co-recruitment of both p53 regulatory enzymes facilitates crosstalk between SIRT1 and HIPK2 at the PML-NB. HIPK2 phosphorylates SIRT1, which in turn inhibits SIRT1 activity through dissociation of AROS. Reduced SIRT1 activity enables efficient p53 acetylation, expression of pro-apoptotic p53 target genes and potentiation of the DNA damage-induced cell death response