DNA Repair 4 (2005) 1306–1313 Sirtuins (histone deacetylases III) in the cellular response to DNA damage—Facts and hypotheses Marcin Kruszewski ∗ , Irena Szumiel Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry & Technology, Dorodna 16, 03-195 Warszawa, Poland Received 3 June 2005; received in revised form 24 June 2005; accepted 25 June 2005 Available online 3 August 2005 Abstract 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. © 2005 Elsevier B.V. All rights reserved. Keywords: DNA double strand breaks; Apoptosis; Poly(ADP-ribose) polymerase 1. Introduction In diagrams of functions of various DNA repair sys- tems, DNA usually is presented as a straight line. This, of Abbreviations: CBP, CREB-binding protein; DNA-PK, DNA-dependent protein kinase; DSB, DNA double strand break; FOXO, forkhead box class O; Gadd45, growth arrest and DNA damage response gene; HAT, histone acetyltransferase; HDAC, histone deacetylase; Mn-SOD, manganese super- oxide dismutase; NHEJ, non-homologous end joining; p27/Kip1, cyclin- dependent kinase inhibitor; PARG, poly(ADP-ribose) glycohydrolase; PARP-1, poly(ADP-ribose) polymerase-1; PCAF, p300/CBP-associated fac- tor; Sir, silent information regulator; SIRT1, human homologue of Sir2; SWI/SNF, ATP-dependent chromatin remodeling factors; TRAIL, tumor necrosis factor apoptosis related ligand ∗ Corresponding author. Tel.: +48 22 811 07 36; fax: +48 22 811 07 36. E-mail address: marcinkr@orange.ichtj.waw.pl (M. Kruszewski). course, is a greatly simplified picture. Although DNA is a linear molecule, in eukaryotic cells it is present as a com- plicated structure complexed with numerous proteins, chro- matin. Double-stranded DNA is wound around core histones H2A, H2B, H3, H4, two of each per nucleosome “core”, to form the basic chromatin fibre (reviewed in [1]). Between nucleosomes, a stretch of DNA—linker DNA—binds his- tone H1. Such is the “beads on a string” model of chro- matin. This “basic fibre” is further coiled and supercoiled and stabilised by other, non-histone proteins. Chromatin is a highly dynamic structure, and the degree of condensation locally varies depending on whether the particular DNA frag- ment is to be stored as transcriptionally inactive, or is—on demand—available to be transcribed, replicated or repaired. The condensation–decondensation transition depends on var- 1568-7864/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.dnarep.2005.06.013