Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 31, Pages 11341-11346Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1403737111
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Funding
- Cancer Research U.K. Programme Award [300/A13058]
- Medical Research Council (MRC) grant
- National Institutes of Health [DK062248]
- Cancer Prevention Research Institute of Texas funding [RP110471]
- Centre for Environmental and Molecular Carcinogenesis at MD Anderson
- Structural Genomics Consortium [1097737]
- Canadian Institute for Health Research
- Canada Foundation for Innovation
- Genome Canada
- GlaxoSmithKline
- Pfizer
- Eli Lilly
- Takeda
- Takeda, AbbVie
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Wellcome Trust [092809/Z/10/Z]
- MRC [G0500905, G9400953, G1000807] Funding Source: UKRI
- Cancer Research UK [13058] Funding Source: researchfish
- Medical Research Council [G1000807, G0500905, G9400953] Funding Source: researchfish
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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.
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