Histone deacetylase complexes as caretakers of genome stability

Abstract

Histone deacetylase complexes (HDACs) are powerful regulators of the epigenome. It is now clear that a subset of HDACs also regulate the stability of the genome itself, but not primarily through transcription. Instead, these key HDACs control genome stability more directly by stabilizing enzymes important for DNA mutagenesis and repair, or by modifying histones at sites of DNA damage. Surprisingly, certain HDACs in budding yeast and human cells accelerate the pace of genetic expansions in trinucleotide repeats, the type of mutation that causes Huntington disease. In other words, HDACs promote mutagenesis in some settings. At double-strand breaks, however, the same HDACs in budding yeast help stabilize the genome by facilitating homology-dependent repair. Double-strand breaks can also be repaired without the requirement for homology, and two specific human HDACs are now known to promote this event. These new findings highlight certain HDACs as caretakers of genome stability, and also underscore the potential medical complexities in using HDAC inhibitors for treatment of disease.

Figure 1. Summary of HDACs and HATs described in the text.

Figure 2. Speculative models of HDAC activity during triplet repeat expansions. (A) Gatekeeper hypothesis. The nucleosome structure at triplet repeats (arrows) and changes to histone tail acetylation are shown. Expansion promoting proteins are theorized to have improved access to the TNR DNA upon histone deacetylation. (B) Caretaker hypothesis. Stabilization of expansion promoting proteins (such as Sae2) by deacetylation allows these proteins more opportunity to travel to the trinucleotide repeat and catalyze the expansion.