Human SIRT1 is an NAD+-dependent deacetylase protein that plays a role in cell death/survival, senescence, and endocrine signaling. While its substrates, including p53, have been well characterized, no direct regulators are known. We describe here a nuclear protein, active regulator of SIRT1 (AROS), which directly regulates SIRT1 function. AROS enhanced SIRT1-mediated deacetylation of p53 both in vitro and in vivo, and it inhibited p53-mediated transcriptional activity. AROS activity was abrogated by the SIRT1 inhibitors splitomicin and nicotinamide and by SIRT1 small interfering RNA (siRNA). In addition, AROS was unable to cooperate in p53 inactivation in an AROS-binding-defective SIRT1 mutant. Finally, knockdown of endogenous AROS using an antisense expression vector enhanced p21WAF1 expression and increased both the G0/G1 population and apoptosis in response to DNA damage, while AROS overexpression improved cell survival. To our knowledge, AROS is the first direct SIRT1 regulator to be identified that modulates p53-mediated growth regulation.

On page 267, the following sentence is incorrect: ''Interestingly, the DNA strand is mainly B-like (between C2 0 -endo and O4 0 -endo) except for the deoxynucleotide in the DNA-binding channel, which is between A and B form (C4 0 -exo).'' Instead, the sentence should read ''Interestingly, the DNA strand is B-like in the phosphate-binding pocket and A-like in the DNA-binding channel.''