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

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.

Autophagy and genomic integrity

“…46 Alternatively, autophagy may also provide metabolic precursors for the generation of ATP, which is employed in several steps of DNA repair, 47 as well as regulate the supply of dNTPs for DNA synthesis during repair. 48 By targeting glycogen, lipids and proteins to lysosomes, autophagy guides the breakdown of these macromolecules, thereby producing metabolic precursors that can sustain oxidative phosphorylation and glycolysis.…”

“…Recently, an intricate relationship between histone deacetylases (HDACS) -which are involved in DNA repair and apoptosis, 56,57 -DSB processing and autophagy was shown in budding yeast. 46,58 Treatment with valproic acid (VPA), an HDAC inhibitor, impaired the activation of Rad53 in response to DSBs. In the VPA-treated cells, Mre11, the first factor recruited to DSB sites, remained bound to the DSB site, accompanied by reduced levels of Sae2, which is responsible for removing Mre11 from the DSB region, a step required for the progress of lesion repair.…”

Epigenetic cancer therapy: rationales, targets and drugs

“…Moreover, when yeast cells were incubated in the presence of the HDAC inhibitor valproic acid, the drug specifically counteracted the activation of the ATRmediated DNA damage checkpoint response (Robert et al, 2011). Surprisingly, the effect on DNA damage repair involved the degradation of key recombination proteins by autophagy (Robert et al, 2011).…”

“…Surprisingly, the effect on DNA damage repair involved the degradation of key recombination proteins by autophagy (Robert et al, 2011). These observations were explained by a model where protein acetylation marks DNA recombination proteins for transport to the vacuole and subsequent degradation, and where deacetylation of these factors is required for their stabilization in subnuclear compartments with severely damaged DNA.…”

Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2

“…The clinical activity of HDACis is thought to be due to the more open chromatin structure and potential reactivation of aberrantly suppressed genes, leading to growth arrest, cell differentiation, and apoptosis of tumor cells (Vigushin and Coombes 2002;Balakin et al 2007;Mottet and Castronovo 2008;Shankar and Srivastava 2008;Witt et al 2009;Tan et al 2010). These inhibitors also influence the DNA damage response through acetylation of key DNA repair and checkpoint proteins (Choudhary et al 2009;Robert et al 2011). Still, our knowledge about these inhibitors remains limited; understanding the regulatory mechanism of HDACs is imperative to reveal the therapeutic potential of HDACis.…”