1. CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis
- Author
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Daniela Necchi, Micol Tillhon, Sabrina Sommatis, Tiziana Nardo, Angela Bachi, Ornella Cazzalini, Ennio Prosperi, Lucia Anna Stivala, Ilaria Dutto, Alexander Rapp, M. Cristina Cardoso, and A. Ivana Scovassi
- Subjects
DNA Replication ,DNA Repair ,DNA repair ,DNA-Directed DNA Polymerase ,Genome Integrity, Repair and Replication ,DNA polymerase delta ,RFC2 ,03 medical and health sciences ,0302 clinical medicine ,Replication factor C ,Proliferating Cell Nuclear Antigen ,Genetics ,Humans ,p300-CBP Transcription Factors ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,DNA clamp ,biology ,Acetylation ,DNA ,Molecular biology ,CREB-Binding Protein ,Chromatin ,Proliferating cell nuclear antigen ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,DNA mismatch repair ,Nucleotide excision repair ,DNA Damage - 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.
- Published
- 2014