title: The direct interaction between 53BP1 and MDC1 is required for the recruitment of 53BP1 to sites of damage.
abstract: The DNA damage response mediators, 53BP1 and MDC1, play a central role in checkpoint activation and DNA repair. Here we establish that human 53BP1 and MDC1 interact directly through the tandem BRCT domain of MDC1 and residues 1288-1409 of 53BP1. Following induction of DNA double strand breaks the interaction is reduced, probably due to competition between gamma-H2AX and 53BP1 for the binding of the tandem BRCT domain of MDC1. Furthermore, the MDC1 binding region of 53BP1 is required for focus formation by 53BP1. During mitosis the interaction between 53BP1 and MDC1 is enhanced. The interaction is augmented in a phospho-dependent manner, and the MDC1 binding region of 53BP1 is phosphorylated in vivo in mitotic cells; therefore, it is probably modulated by cell cycle-regulated kinases. Our results demonstrate that the 53BP1-MDC1 interaction per se is required for the recruitment of 53BP1 to sites of DNA breaks, which is known to be crucial for an efficient activation of the DNA damage response. Moreover, the results presented here suggest that the interaction between 53BP1 and MDC1 plays a role in the regulation of mitosis.
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel and the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Eliezer
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel and the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.
authors.forename: Liron
authors.initials: L
authors.lastname: Argaman
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel and the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rhie
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel and the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom.
authors.forename: Aidan J
authors.initials: AJ
authors.lastname: Doherty
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel and the Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom. Electronic address: goldbergm@vms.huji.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D053960:DNA Breaks; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1