title: Tandem protein interaction modules organize the ubiquitin-dependent response to DNA double-strand breaks.
abstract: The response to DNA double-strand breaks (DSBs) entails the hierarchical recruitment of proteins orchestrated by ATM-dependent phosphorylation and RNF8-mediated chromatin ubiquitylation. As in most ubiquitin-dependent processes, the ordered accumulation of DNA repair factors at the break site relies on ubiquitin-binding domains (UBDs). However, how UBDs select their ligands is poorly understood, and therefore we sought to uncover the basis for selectivity in the ubiquitin-dependent DSB response. We show that RNF168, its paralog RNF169, RAD18, and the BRCA1-interacting RAP80 protein accumulate at DSB sites through the use of bipartite modules composed of UBDs juxtaposed to peptide motifs that provide specificity. These sequences, named LR motifs (LRMs), are transferable, and we show that the RNF169 LRM2 binds to nucleosomes, the substrates of RNF168. The LRM-based selection of ligands is a parsimonious means to build a highly discrete ubiquitin-based signaling pathway such as the DNA damage response.
authors: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors: Stephanie
authors: S
authors: Panier
authors: Yosuke
authors: Y
authors: Ichijima
authors: Amélie
authors: A
authors: Fradet-Turcotte
authors: Charles C Y
authors: CC
authors: Leung
authors: Lilia
authors: L
authors: Kaustov
authors: Cheryl H
authors: CH
authors: Arrowsmith
authors: Daniel
authors: D
authors: Durocher
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D056488:Histone Chaperones; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D025801:Ubiquitin / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D009687:Nuclear Proteins; C485954:RAD18 protein, human; C466234:UIMC1 protein, human; D025801:Ubiquitin; C535210:RNF168 protein, human; C572547:RNF169 protein, human; D044767:Ubiquitin-Protein Ligases