title: Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor.
abstract: The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.
authors: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom;
authors: Simon M
authors: SM
authors: Carr
authors: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom;
authors: Shonagh
authors: S
authors: Munro
authors: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom;
authors: Lykourgos-Panagiotis
authors: LP
authors: Zalmas
authors: Structural Genomics Consortium Oxford, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom; and.
authors: Oleg
authors: O
authors: Fedorov
authors: Structural Genomics Consortium Oxford, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom; and.
authors: Catrine
authors: C
authors: Johansson
authors: Structural Genomics Consortium Oxford, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom; and.
authors: Tobias
authors: T
authors: Krojer
authors: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 77030.
authors: Cari A
authors: CA
authors: Sagum
authors: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 77030.
authors: Mark T
authors: MT
authors: Bedford
authors: Structural Genomics Consortium Oxford, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom; and.
authors: Udo
authors: U
authors: Oppermann
authors: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom; nick.lathangue@oncology.ox.ac.uk.
authors: Nicholas B
authors: NB
authors: La Thangue
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D016160:Retinoblastoma Protein; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D008239:Lysine