converse, deacetylation of PTEN by SIRT1 deacetylase and, by HDAC1, can stimulate its activity. APE1/Ref-1 (APEX1) is a multifunctional protein possessing both DNA repair activity (on abasic and single-strand break sites) and transcriptional regulatory activity associated with oxidative stress. APE1/Ref-1 is acetylated by PCAF; on the converse, it is stably associated with and deacetylated by Class I HDACs. The acetylation state of APE1/Ref-1 does not appear to affect its DNA repair activity, but it does regulate its transcriptional activity such as its ability to bind to the PTH promoter and initiate transcription of the parathyroid hormone gene. NF-κB is a key transcription factor and effector molecule involved in responses to cell stress, consisting of a p50/p65 heterodimer. The p65 subunit is controlled by acetylation via PCAF and by deacetylation via HDAC3 and HDAC6. These are just some examples of constantly emerging non-histone, non-chromatin roles for HDACs. Neurodegenerative diseases Inherited mutations in the gene encoding FUS, an RNA/DNA binding protein, are causally linked to amyotrophic lateral sclerosis (ALS). FUS has a pivotal role in the DNA damage response involving its direct interaction with histone deacetylase 1 (HDAC1). ALS mutant FUS proteins are defective in the DNA damage response and in recombinational DNA repair, and also show reduced interaction with HDAC1. Ataxia-telangiectasia is due to mutation in the Atm gene. Wild-type Atm encodes a protein kinase employed in chromatin remodeling and in epigenetic alterations that are required for repairing DNA double-strand breaks. Atm mutation causes neurons to accumulate nuclear histone deacetylase 4 (HDAC4) resulting in increased histone deacetylation and altered neuronal gene expression that likely contributes to the neurodegeneration characteristic of ataxia-telangiectasia. HDAC inhibitors Histone deacetylase inhibitors (HDIs) have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example, valproic acid. In more recent times, HDIs are being studied as a mitigator or treatment for neurodegenerative diseases. Also in recent years, there has been an effort to develop HDIs for cancer therapy. Vorinostat (SAHA) was FDA approved in 2006 for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) that have failed previous treatments. A second HDI, Istodax (romidepsin), was approved in 2009 for patients with CTCL. The exact mechanisms by which the compounds may work are unclear, but epigenetic pathways are proposed. In addition, a clinical trial is studying valproic acid effects on the latent pools of HIV in infected persons.