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.

The small heterodimer partner SHP (NR0B2) is an unusual nuclear receptor that lacks the typical DNA binding domain common to most nuclear receptors. SHP has been reported to act as a corepressor for several nuclear receptors, but its exact mechanism of action is still elusive. Here we show that SHP can interact with the liver X receptors LXRα (NR1H3) and LXRβ (NR1H2), as demonstrated by glutathione-S-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, SHP inhibits the expression of an artificial reporter driven by an LXR-response element and represses the transcriptional activation by LXR of the human ATP-binding cassette transporter 1 (ABCA1) promoter. Treatment of Caco-2 cells with bile acids, which activate farnesoid X receptor and subsequently induce SHP, leads to the repression of the human ABCG1 gene, an established LXR target gene. These results demonstrate that SHP is able to interact with LXR and to modulate its transcriptional activity.

The scavenger receptor class B type I (SR‐BI), which mediates selective cellular cholesterol uptake from high‐density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. The orphan nuclear receptor liver receptor homolog 1 (LRH‐1) and SR‐BI are co‐expressed in liver and ovary, suggesting that LRH‐1 might control the expression of SR‐BI in these tissues. LRH‐1 induces human and mouse SR‐BI promoter activity by binding to an LRH‐1 response element in the promoter. Retroviral expression of LRH‐1 robustly induces SR‐BI, an effect associated with histone H3 acetylation on the SR‐BI promoter. The decrease in SR‐BI mRNA levels in livers of LRH‐1^+/− animals provides in vivo evidence that LRH‐1 regulates SR‐BI expression. Our data demonstrate that SR‐BI is an LRH‐1 target gene and underscore the pivotal role of LRH‐1 in reverse cholesterol transport.