SIRT1, the most widely studied of the protein family known as sirtuins, is a histone deacetylase that has been implicated in regulation of aging in mammals. Activators of SIRT1, such as resveratrol, have been demonstrated to extend the lifespan as well as boost mitochondrial function in mice.

More recently, SIRT1 has been demonstrated to regulate p53 function: deacetylation by SIRT1 makes p53 less active, thereby decreasing apoptosis in response to specific types of DNA-damaging stress (e.g., ionizing radiation). This would be advantageous in some circumstances and deleterious in others, depending on the relative value placed on cellular survival vs. elimination of potentially neoplastic cells. Thus, this observation raises questions regarding how SIRT1 is itself regulated.

In back-to-back papers in Nature earlier this year, two labs report the discovery that the DBC1 (“deleted in breast cancer”) protein specifically inhibits SIRT1, in turn increasing p53 activity and thereby stimulating p53-mediated apoptosis in response to genotoxic stress. Of the two papers, Zhao et al. have the more elaborate abstract, reproduced below; Kim et al. reach similar conclusions:

Negative regulation of the deacetylase SIRT1 by DBC1

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53. These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. 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 directly modulate metabolic responses. 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.

The fact that the DBC1 protein was originally identified as one that is frequently deleted in breast tumors suggests that there are indeed tissues in which unchecked SIRT1 deacetylation of p53 would be a bad thing (i.e., in which it makes sense to kill off damaged cells, even at a cost to regenerative capacity — another example of the evolutionary tradeoffs between regenerative capacity and tumor suppression).

One obvious question is whether DBC1 is also commonly deleted in other epithelial tumors; if so, is there a pattern in the tissue types that develop such tumors? e.g., perhaps DBC1 is particularly important in epithelial populations that, like the breast, lie dormant for much of the lifespan but possess the latent ability to proliferate rapidly in response to hormones — in cells like these, it makes sense to have a relatively “hair-trigger” apoptotic response to potentially carcinogenic insults. In less proliferative tissues, however, the system might be tuned quite differently, with DBC1 levels set relatively low in order to preserve self-renewal capacity even after a manageable level of genotoxic damage.

Next step, of course: What regulates DBC1?