The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

Abstract

Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD+ dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD+, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization.

Metabolic and gene expression hallmarks of seed germination uncovered by sodium butyrate in Medicago truncatula

“…So far, information concerning the interplay between oxidative stress and ER stress in the specific context of seed germination is missing. However, based on these findings, we cannot and sensitizing cells to genotoxic agents (Roos & Krumm, 2016). In Pagano et al, 2017).…”

“…truncatula seeds at the radicle protrusion stage (Figure a). In animal cells, HDAC inhibitors play contrasting roles in DDR, by promoting DNA repair through chromating relaxation, suppressing the catalytic activity of specific repair complexes, and sensitizing cells to genotoxic agents (Roos & Krumm, ). In our system, comet assay provided evidence of DNA damage accumulation in NaB‐treated seeds at the radicle protrusion stage, in agreement with Pagano et al () who reported genotoxic damage in M .…”

The role of histone deacetylase inhibitors in regulation of Akt/GSK-3β signaling pathway in mice following transient focal cerebral ischemia

“…Studies have shown that HDACI can inhibit the catalytic activity of HDAC, change the chromosome structure, activate the gene transcription, correct the chromosomes from "closed" to "open" state, play a neuroprotective role, including: inhibition of neuronal apoptosis, regulation of microglia/macrophage polarization, reduction of inflammatory response, promotion of nerve regeneration 5,20 . 21,22 . Our results also confirm that HDACI has a protective effect in cerebral ischemia reperfusion, which may be associated with activation of Akt/GSK-3β pathway.…”

Sirtuins and DNA damage repair: SIRT7 comes to play

“…Evidence in different organisms strongly suggests that nuclear sirtuins are particularly relevant in the signaling pathways that repair DSBs: non-homologous end joining (NHEJ) and homologous recombination (HR) 19 (Fig. 2).…”