DNA-damage-responsive acetylation of pRb regulates binding to E2F-1.
The pRb (retinoblastoma protein) tumour suppressor protein has a crucial role in regulating the G1- to S-phase transition, and its phosphorylation by cyclin-dependent kinases is an established and important mechanism in controlling pRb activity. In addition, the targeted acetylation of lysine (K) residues 873/874 in the carboxy-terminal region of pRb located within a cyclin-dependent kinase-docking site hinders pRb phosphorylation and thereby retains pRb in an active state of growth suppression. Here, we report that the acetylation of pRb K873/874 occurs in response to DNA damage and that acetylation regulates the interaction between the C-terminal E2F-1-specific domain of pRb and E2F-1. These results define a new role for pRb acetylation in the DNA damage signalling pathway, and suggest that the interaction between pRb and E2F-1 is controlled by DNA-damage-dependent acetylation of pRb.
Markham
Douglas
D
Laboratory of Cancer Biology, Nuffield Department of Clinical Laboratory Sciences, Medical Sciences Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Munro
Shonagh
S
Soloway
Judith
J
O'Connor
Darran P
DP
La Thangue
Nicholas B
NB
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D004249:DNA Damage; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005047:Etoposide / Q000494:pharmacology; D005456:Fluorescent Dyes; D005786:Gene Expression Regulation; D006801:Humans; D007211:Indoles; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D050687:E2F1 Transcription Factor; D005456:Fluorescent Dyes; D007211:Indoles; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D016160:Retinoblastoma Protein; C007293:DAPI; D005047:Etoposide; D008156:Luciferases