Possible Role for Deacetylation in DNA Damage Response

Science's STKE  10 Jul 2007:
Vol. 2007, Issue 394, pp. tw247
DOI: 10.1126/stke.3942007tw247

An intricate signaling system exists in cells to detect damaged DNA, delay progression through the cell cycle, and initiate repair of the damage. Yuan et al. provide evidence for a new layer of regulation to this process, showing that the NBS1 protein is subject to regulation by acetylation and deacetylation on lysine residues. NBS stands for Nijmegen breakage syndrome, the disease caused by mutations in the gene encoding NBS1. Affected individuals show a range of symptoms that include sensitivity to radiation and predisposition to lymphoid cancers. NBS1 functions in a protein complex known as MRN (MRE-11-RAD50-NBS1) that participates in sensing and repairing DNA damage. NBS1 was acetylated in cells transfected with various acetyltransferases, and acetylation was enhanced if cells were treated with inhibitors of class III histone deacetylases (HDACs). Acetylation of NBS1 by transfected acetylases was also enhanced if the HDAC SIRT1 was depleted with RNAi. Modification of NBS1 by phosphorylation is critical for sensing of DNA damage and for the cell cycle checkpoint mechanism that delays DNA replication until repair is completed. Overexpression of an acetylase and consequent acetylation of NBS1 decreased phosphorylation of NBS1. Transfected acetylase also inhibited the cell cycle checkpoint function that prevents DNA synthesis after exposure of cells to ionizing radiation. This effect was not observed, though, when cells expressed a mutant of NBS1 resistant to acetylation. In mouse embryo fibroblasts that did not express the SIRT1 deacetylase, in which NBS1 was expected to be highly acetylated and thus poorly phosphorylated, checkpoint function was also compromised. Thus, the authors propose that crosstalk between acetylation and phosphorylation mechanisms may regulate responses to DNA damage.

Z. Yuan, X. Zhang, N. Sengupta, W. S. Lane, E. Seto, SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol. Cell 27, 149-162 (2007). [PubMed]