Negative regulation of the deacetylase SIRT1 by DBC1

SIRT1 is an NAD- dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing(1-15). The tumour suppressor p53 represents the first non- histone substrate functionally regulated by acetylation and deacetylation(16,17); we and others previously found that SIRT1 promotes cell survival by deacetylating p53 ( refs 4-6). These results were further supported by the fact that p53 hyperacetylation and increased radiation- induced apoptosis were observed in Sirt1- deficient mice(10). Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53- independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1 alpha directly modulate metabolic responses(1-15). These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 ( deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1- mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference ( RNAi) stimulates SIRT1- mediated deacetylation of p53 and inhibits p53- dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53- mediated apoptosis through specific inhibition of SIRT1.