HDACs link the DNA damage response, processing of double-strand breaks and autophagy

Thomas Robert, Fabio Vanoli, Irene Chiolo, Ghadeer Shubassi, Kara A. Bernstein, Rodney Rothstein, Oronza A. Botrugno, Dario Parazzoli, Amanda Oldani, Saverio Minucci () and Marco Foiani ()
Additional contact information
Thomas Robert: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy
Fabio Vanoli: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy
Irene Chiolo: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy
Ghadeer Shubassi: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy
Kara A. Bernstein: Columbia University Medical Center
Rodney Rothstein: Columbia University Medical Center
Oronza A. Botrugno: European Institute of Oncology, IFOM-IEO campus, Milan 20139, Italy
Dario Parazzoli: Cogentech, Milan 20139, Italy
Amanda Oldani: Cogentech, Milan 20139, Italy
Saverio Minucci: European Institute of Oncology, IFOM-IEO campus, Milan 20139, Italy
Marco Foiani: Fondazione IFOM (Istituto FIRC di Oncologia Molecolare), IFOM-IEO Campus, via Adamello 16, Milan 20139, Italy

Nature, 2011, vol. 471, issue 7336, 74-79

Abstract: Abstract Protein acetylation is mediated by histone acetyltransferases (HATs) and deacetylases (HDACs), which influence chromatin dynamics, protein turnover and the DNA damage response. ATM and ATR mediate DNA damage checkpoints by sensing double-strand breaks and single-strand-DNA–RFA nucleofilaments, respectively. However, it is unclear how acetylation modulates the DNA damage response. Here we show that HDAC inhibition/ablation specifically counteracts yeast Mec1 (orthologue of human ATR) activation, double-strand-break processing and single-strand-DNA–RFA nucleofilament formation. Moreover, the recombination protein Sae2 (human CtIP) is acetylated and degraded after HDAC inhibition. Two HDACs, Hda1 and Rpd3, and one HAT, Gcn5, have key roles in these processes. We also find that HDAC inhibition triggers Sae2 degradation by promoting autophagy that affects the DNA damage sensitivity of hda1 and rpd3 mutants. Rapamycin, which stimulates autophagy by inhibiting Tor, also causes Sae2 degradation. We propose that Rpd3, Hda1 and Gcn5 control chromosome stability by coordinating the ATR checkpoint and double-strand-break processing with autophagy.

Date: 2011
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DOI: 10.1038/nature09803

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