title: Serine ADP-Ribosylation Depends on HPF1.
abstract: ADP-ribosylation (ADPr) regulates important patho-physiological processes through its attachment to different amino acids in proteins. Recently, by precision mapping on all possible amino acid residues, we identified histone serine ADPr marks in the DNA damage response. However, the biochemical basis underlying this serine modification remained unknown. Here we report that serine ADPr is strictly dependent on histone PARylation factor 1 (HPF1), a recently identified regulator of PARP-1. Quantitative proteomics revealed that serine ADPr does not occur in cells lacking HPF1. Moreover, adding HPF1 to in vitro PARP-1/PARP-2 reactions is necessary and sufficient for serine-specific ADPr of histones and PARP-1 itself. Three endogenous serine ADPr sites are located on the PARP-1 automodification domain. Further identification of serine ADPr on HMG proteins and hundreds of other targets indicates that serine ADPr is a widespread modification. We propose that O-linked protein ADPr is the key signal in PARP-1/PARP-2-dependent processes that govern genome stability.
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Bonfiglio
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fontana
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Colby
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Gibbs-Seymour
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
authors.forename: Ilian
authors.initials: I
authors.lastname: Atanassov
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Edward
authors.initials: E
authors.lastname: Bartlett
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Roko
authors.initials: R
authors.lastname: Zaja
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. Electronic address: ivan.ahel@path.ox.ac.uk.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ahel
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany. Electronic address: imatic@age.mpg.de.
authors.forename: Ivan
authors.initials: I
authors.lastname: Matic
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D040901:Proteomics / Q000379:methods; D012694:Serine; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C000621618:HPF1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D000246:Adenosine Diphosphate Ribose; D012694:Serine; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ADP-ribosylation; DNA damage; HPF1; PARP-1; PARP-2; genome stability; histones; proteomics; serine ADP-ribosylation