title: 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.
authors.affiliation: Institute of Toxicology, Medical Center of the University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany wynandpaulroos@yahoo.co.uk.
authors.forename: Wynand Paul
authors.initials: WP
authors.lastname: Roos
authors.affiliation: Institute of Toxicology, Medical Center of the University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Krumm
mesh_terms: D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D059766:DNA End-Joining Repair; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000502:physiology*; D059765:Homologous Recombination; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D037761:Sirtuins; D006655:Histone Deacetylases