Editors' ChoiceCell Biology

Eliminating Unnecessary Repair Machinery?

Science Signaling  08 Mar 2011:
Vol. 4, Issue 163, pp. ec66
DOI: 10.1126/scisignal.4163ec66

Although it is best known for its role in regulating chromatin dynamics, new roles for protein acetylation as a reversible posttranslational modification have continued to emerge. Noting that key DNA repair and checkpoint proteins are acetylated, Robert et al. investigated the role of acetylation in the DNA damage response. Exposure to the histone deacetylase (HDAC) inhibitor valproic acid (VPA) inhibited double-strand break (DSB) resection and Mec1 (the yeast ortholog of human checkpoint kinase ATR) signaling in budding yeast, and analysis of early events in DSB processing revealed that the abundance of two proteins involved in DSB resection, Sae2 and Exo1, was markedly reduced. Acetylation has been implicated in degradation of proteins by autophagy, and various analyses indicated that VPA induced autophagy in yeast, as it does in mammals. VPA enhanced the amount of HA-tagged Sae2 immunoprecipitated with anti-acetyl-Lysine antibodies, and a combination of pharmacological and genetic analysis indicated that autophagy contributed to Sae2 degradation. The effects of VPA on Sae2 stability, DSB processing, and checkpoint activation were replicated in yeast bearing mutations in the HDACs Hda1 and Rpd3, whereas loss of the histone acetyltransferase Gcn3 attenuated the VPA-mediated decrease in Sae2 stability. The authors thus conclude that acetylation coordinates the ATR checkpoint and DSB processing with autophagy. Potenski and Klein provide commentary.

T. Robert, F. Vanoli, I. Chiolo, G. Shubassi, K. A. Bernstein, R. Rothstein, O. A. Botrugno, D. Parazzoli, A. Oldani, S. Minucci, M. Foiani, HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature 471, 74–79 (2011). [PubMed]

C. J. Potenski, H. L. Klein, The expanding arena of DNA repair. Nature 471, 48–49 (2011). [PubMed]

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