title: 5mC-hydroxylase activity is influenced by the PARylation of TET1 enzyme.
abstract: 5-hydroxymethylcytosine is a new epigenetic modification deriving from the oxidation of 5-methylcytosine by the TET hydroxylase enzymes. DNA hydroxymethylation drives DNA demethylation events and is involved in the control of gene expression. Deregulation of TET enzymes causes developmental defects and is associated with pathological conditions such as cancer. Little information thus far is available on the regulation of TET activity by post-translational modifications. Here we show that TET1 protein is able to interact with PARP-1/ARTD1 enzyme and is target of both noncovalent and covalent PARylation. In particular, we have demonstrated that the noncovalent binding of ADP-ribose polymers with TET1 catalytic domain decreases TET1 hydroxylase activity while the covalent PARylation stimulates TET1 enzyme. In addition, TET1 activates PARP-1/ARTD1 independently of DNA breaks. Collectively, our results highlight a complex interplay between PARylation and TET1 which may be helpful in coordinating the multiple biological roles played by 5-hydroxymethylcytosine and TET proteins.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome and Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciccarone
authors.affiliation: Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome and Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Valentini
authors.affiliation: Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome and Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zampieri
authors.affiliation: Department of Cellular Biotechnologies and Hematology, "Sapienza" University of Rome and Pasteur Institute-Fondazione Cenci Bolognetti, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Caiafa
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D008969:Molecular Sequence Data; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D005982:Glutathione Transferase
keywords: 5hmC; PARylation; TET1