title: MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner.
abstract: The cellular response to DNA damage is essential for maintenance of genomic stability. MDC1 is a key member of the DNA damage response. It is an adaptor protein that binds and recruits proteins to sites of DNA damage, a crucial step for a proper response. MDC1 contains several protein-protein interacting modules, including a tandem BRCT domain that mediates various interactions involving MDC1. Here we demonstrate that MDC1 binds directly to RAP80, which is a DNA damage response protein that recruits BRCA1 to sites of damage. The interaction between MDC1 and RAP80 requires the tandem BRCT domain of MDC1 and the ubiquitin-interacting motifs of RAP80. Moreover, the interaction depends on UBC13, an E2 ubiquitin ligase that catalyzes K63-linked poly-ubiquitin chain formation. The results highly propose that the interaction between MDC1 and RAP80 depends on a ubiquitylation event, which we found to take place on K-1977 of MDC1. This study provides the first evidence that interactions involving MDC1 can be regulated by ubiquitylation.
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Strauss
authors.forename: Tomer
authors.initials: T
authors.lastname: Halevy
authors.forename: Michal
authors.initials: M
authors.lastname: Macarov
authors.forename: Liron
authors.initials: L
authors.lastname: Argaman
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins; D057809:HEK293 Cells; D056488:Histone Chaperones; D006801:Humans; D008239:Lysine / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C413163:MDC1 protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D015534:Trans-Activators; C466234:UIMC1 protein, human; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; D008239:Lysine