title: DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair.
abstract: HIC1 (hypermethylated in cancer 1) is a tumor suppressor gene frequently epigenetically silenced in human cancers. HIC1 encodes a transcriptional repressor involved in the regulation of growth control and DNA damage response. We previously demonstrated that HIC1 can be either acetylated or SUMOylated on lysine 314. This deacetylation/SUMOylation switch is governed by an unusual complex made up of SIRT1 and HDAC4 which deacetylates and thereby favors SUMOylation of HIC1 by a mechanism not yet fully deciphered. This switch regulates the interaction of HIC1 with MTA1, a component of the NuRD complex and potentiates the repressor activity of HIC1. Here, we show that HIC1 silencing in human fibroblasts impacts the repair of DNA double-strand breaks whereas ectopic expression of wild-type HIC1, but not of nonsumoylatable mutants, leads to a reduced number of γH2AX foci induced by etoposide treatment. In this way, we demonstrate that DNA damage leads to (i) an enhanced HDAC4/Ubc9 interaction, (ii) the activation of SIRT1 by SUMOylation (Lys-734), and (iii) the SUMO-dependent recruitment of HDAC4 by SIRT1 which permits the deacetylation/SUMOylation switch of HIC1. Finally, we show that this increase of HIC1 SUMOylation favors the HIC1/MTA1 interaction, thus demonstrating that HIC1 regulates DNA repair in a SUMO-dependent way. Therefore, epigenetic HIC1 inactivation, which is an early step in tumorigenesis, could contribute to the accumulation of DNA mutations through impaired DNA repair and thus favor tumorigenesis.
authors: CNRS-UMR 8161, Université de Lille Nord de France, Institut Pasteur de Lille, IFR 142, 1 rue Calmette, BP447, 59017 Lille Cedex, France.
authors: Vanessa
authors: V
authors: Dehennaut
authors: Ingrid
authors: I
authors: Loison
authors: Marion
authors: M
authors: Dubuissez
authors: Joe
authors: J
authors: Nassour
authors: Corinne
authors: C
authors: Abbadie
authors: Dominique
authors: D
authors: Leprince
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D019556:COS Cells; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects / Q000502:physiology*; D015534:Trans-Activators
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D005047:Etoposide; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex