title: Molecular dissection of the interaction between HIC1 and SIRT1.
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, cell survival and DNA damage response. The deacetylase SIRT1 regulates the repressive capacity of HIC1 in several fashions. First SIRT1 interacts with the BTB/POZ domain of HIC1 to form a transcriptional repression complex that prevents the transcription of SIRT1 itself. SIRT1 is also responsible of the deacetylation of the lysine 314 of HIC1 that allows its subsequent SUMOylation which in turn favors its interaction with the NuRD complex. To better understand the interplay between HIC1 and SIRT1, we performed co-immunoprecipitation experiments to define the domains essential for the HIC1/SIRT1 interaction. We demonstrated that the isolated four last zinc fingers of HIC1 were capable to interact with SIRT1 and that the amino-acids 610-677 of SIRT1 encompassing the ESA region of the deacetylase were crucial for the HIC1/SIRT1 interaction and HIC1 deacetylation. Finally we demonstrated that this interaction mainly depends on CKII-mediated phosphorylation of SIRT1 serine 659/661 which occurs upon DNA damage. Therefore, our results demonstrate that the activating acetylation to SUMOylation switch of HIC1 is favored by genotoxic stresses to regulate the DNA damage response.
authors.affiliation: CNRS-UMR 8161, Institut de Biologie de Lille, Université de Lille Nord de France, Institut Pasteur de Lille, IFR 142, 1 rue Calmette, BP447, 59017 Lille Cedex, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dehennaut
authors.forename: Ingrid
authors.initials: I
authors.lastname: Loison
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pinte
authors.forename: Dominique
authors.initials: D
authors.lastname: Leprince
mesh_terms: D000107:Acetylation; D004249:DNA Damage; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D012694:Serine / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D016335:Zinc Fingers
chemical_list: C499808:HIC1 protein, human; D051741:Kruppel-Like Transcription Factors; D012694:Serine; C447939:SIRT1 protein, human; D056564:Sirtuin 1