title: CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis.
abstract: The proliferating cell nuclear antigen (PCNA) protein serves as a molecular platform recruiting and coordinating the activity of factors involved in multiple deoxyribonucleic acid (DNA) transactions. To avoid dangerous genome instability, it is necessary to prevent excessive retention of PCNA on chromatin. Although PCNA functions during DNA replication appear to be regulated by different post-translational modifications, the mechanism regulating PCNA removal and degradation after nucleotide excision repair (NER) is unknown. Here we report that CREB-binding protein (CBP), and less efficiently p300, acetylated PCNA at lysine (Lys) residues Lys13,14,77 and 80, to promote removal of chromatin-bound PCNA and its degradation during NER. Mutation of these residues resulted in impaired DNA replication and repair, enhanced the sensitivity to ultraviolet radiation, and prevented proteolytic degradation of PCNA after DNA damage. Depletion of both CBP and p300, or failure to load PCNA on DNA in NER deficient cells, prevented PCNA acetylation and degradation, while proteasome inhibition resulted in accumulation of acetylated PCNA. These results define a CBP and p300-dependent mechanism for PCNA acetylation after DNA damage, linking DNA repair synthesis with removal of chromatin-bound PCNA and its degradation, to ensure genome stability.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cazzalini
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sommatis
authors.affiliation: Institute of Molecular Genetics, National Research Council (CNR), Pavia 27100, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Tillhon
authors.affiliation: Institute of Molecular Genetics, National Research Council (CNR), Pavia 27100, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dutto
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Milan 20100, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: Technische Universität Darmstadt, Darmstadt 64287, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rapp
authors.affiliation: Institute of Molecular Genetics, National Research Council (CNR), Pavia 27100, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.affiliation: Institute of Molecular Genetics, National Research Council (CNR), Pavia 27100, Italy.
authors.forename: A Ivana
authors.initials: AI
authors.lastname: Scovassi
authors.affiliation: Department of Drug Sciences, University of Pavia, Pavia 27100, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Necchi
authors.affiliation: Technische Universität Darmstadt, Darmstadt 64287, Germany.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Cardoso
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia 27100, Italy.
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Stivala
authors.affiliation: Institute of Molecular Genetics, National Research Council (CNR), Pavia 27100, Italy prosperi@igm.cnr.it.
authors.forename: Ennio
authors.initials: E
authors.lastname: Prosperi
mesh_terms: D000107:Acetylation; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D050882:CREB-Binding Protein; D002843:Chromatin; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D018809:Proliferating Cell Nuclear Antigen; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor