Sirtuins (histone Deacetylases III) in the Cellular Response to DNA Damage--facts and Hypotheses

Histone deacetylases (HDAC) are an important member of a group of enzymes that modify chromatin conformation. Homologues of the yeast gene SIR2 in mammalian cells code type III histone deacetylases (HDAC III, sirtuins), dependent on NAD(+) and inhibited by nicotinamide. In yeast cells, Sir2 participates in repression of transcriptional activity and in DNA double strand break repair. It is assumed that certain sirtuins may play a similar role in mammalian cells, by modifying chromatin structure and thus, altering the accessibility of the damaged sites for repair enzymes. A relation between poly(ADP-ribosylation) and sirtuin function in cells with damaged DNA has been also postulated. Interconnections between NAD(+) metabolism, poly(ADP-ribosylation), DNA repair and gene expression should allow to modulate the cellular response to agents that damage DNA. Preliminary results, reviewed in this paper indicate that such possibility exists. We propose a hypothetical mechanism of sirtuin participation in DSB repair. It is based on the assumption that activation of PARP at the sites of DNA strand breaks leads to a local increase in nicotinamide concentration. Nicotinamide then inhibits sirtuins exactly at the site of DNA strand break. At present, however, there are no data directly confirming the effect of sirtuin inhibition on DSB repair processes in mammalian cells. Nevertheless, a connection between the acetylation status of histones and repair of DNA breaks has recently been found, indicating that all HDAC classes may modulate DNA repair processes. In addition, sirtuins exert an anti-apoptotic action in various cell types. Hence, it is possible to sensitise cells to apoptosis-inducing agents by sirtuin inhibitors.