DNA double-strand breaks lead to activation of hypermethylated in cancer 1 (HIC1) by SUMOylation to regulate DNA repair.
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.
Mesh Terms:
Acetylation, Animals, Antineoplastic Agents, Phytogenic, COS Cells, Cell Transformation, Neoplastic, Cercopithecus aethiops, DNA Breaks, Double-Stranded, DNA Repair, Etoposide, Fibroblasts, Histone Deacetylases, Humans, Kruppel-Like Transcription Factors, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Mutation, Repressor Proteins, Sirtuin 1, Sumoylation
Acetylation, Animals, Antineoplastic Agents, Phytogenic, COS Cells, Cell Transformation, Neoplastic, Cercopithecus aethiops, DNA Breaks, Double-Stranded, DNA Repair, Etoposide, Fibroblasts, Histone Deacetylases, Humans, Kruppel-Like Transcription Factors, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Mutation, Repressor Proteins, Sirtuin 1, Sumoylation
J. Biol. Chem.
Date: Apr. 12, 2013
PubMed ID: 23417673
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