title: p38 MAPK- and Akt-mediated p300 phosphorylation regulates its degradation to facilitate nucleotide excision repair.
abstract: Besides the primary histone acetyltransferase (HAT)-mediated chromatin remodeling function, co-transcriptional factor, p300, is also known to play a distinct role in DNA repair. However, the exact mechanism of p300 function in DNA repair has remained unclear and difficult to discern due to the phosphorylation and degradation of p300 in response to DNA damage. Here, we have demonstrated that p300 is only degraded in the presence of specific DNA lesions, which are the substrates of nucleotide excision repair (NER) pathway. In contrast, DNA double-strand breaks fail to degrade p300. Degradation is initiated by phosphorylation of p300 at serine 1834, which is catalyzed by the cooperative action of p38 mitogen-activated protein kinases and Akt kinases. In depth, functional analysis revealed that (i) p300 and CBP act redundantly in repairing ultraviolet (UV) lesions, (ii) the phosphorylation of p300 at S1834 is critical for efficient removal of UV-induced cyclobutane pyrimidine dimers and (iii) p300 is recruited to DNA damage sites located within heterochromatin. Taken together, we conclude that phosphorylated p300 initially acetylates histones to relax heterochromatin to allow damage recognition factors access to damage DNA. Thereupon, p300 is promptly degraded to allow the sequential recruitment of downstream repair proteins for successful execution of NER.
authors.affiliation: Department of Radiology, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. qi-en.wang@osumc.edu
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
authors.forename: Chunhua
authors.initials: C
authors.lastname: Han
authors.forename: Ran
authors.initials: R
authors.lastname: Zhao
authors.forename: Gulzar
authors.initials: G
authors.lastname: Wani
authors.forename: Qianzheng
authors.initials: Q
authors.lastname: Zhu
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.forename: Aruna
authors.initials: A
authors.lastname: Battu
authors.forename: Ira
authors.initials: I
authors.lastname: Racoma
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sharma
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Wani
mesh_terms: D050882:CREB-Binding Protein / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005047:Etoposide / Q000633:toxicity; D006801:Humans; D010766:Phosphorylation; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011839:Radiation, Ionizing; D012694:Serine / Q000378:metabolism; D014466:Ultraviolet Rays; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D050882:CREB-Binding Protein; D002843:Chromatin; D002945:Cisplatin; D004268:DNA-Binding Proteins; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099224:p300-CBP-Associated Factor; C117669:DDB2 protein, human; C494363:CREBBP protein, human