p300/CBP-associated factor drives DEK into interchromatin granule clusters.
DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.
Cleary
Joanne
J
Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor, Michigan 48109-0640, USA.
Sitwala
Kajal V
KV
Khodadoust
Michael S
MS
Kwok
Roland P S
RP
Mor-Vaknin
Nirit
N
Cebrat
Marek
M
Cole
Philip A
PA
Markovitz
David M
DM
D000107:Acetylation; D000123:Acetyltransferases / Q000502:physiology*; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D042581:Intranuclear Space / Q000378:metabolism*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D051548:Histone Acetyltransferases; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C084738:DEK protein, human; C494363:CREBBP protein, human