title: RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling.
abstract: Cellular DNA double-strand break-repair pathways have evolved to protect the integrity of the genome from a continual barrage of potentially detrimental insults. Inherited mutations in genes that control this process result in an inability to properly repair DNA damage, ultimately leading to developmental defects and also cancer predisposition. Here, we describe a patient with a previously undescribed syndrome, which we have termed RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), whose cells lack an ability to recruit 53BP1 to sites of DNA double-strand breaks. As a consequence, cells derived from this patient exhibit a hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end-joining in the recombined switch regions. Sequencing of TP53BP1 and other genes known to regulate ionizing radiation-induced 53BP1 foci formation in this patient failed to detect any mutations. Therefore, these data indicate the existence of a DNA double-strand break-repair protein that functions upstream of 53BP1 and contributes to the normal development of the human immune system.
authors.affiliation: Cancer Research UK, Institute for Cancer Studies, Birmingham University, Vincent Drive, Edgbaston, Birmingham, United Kingdom. g.s.stewart@bham.ac.uk
authors.forename: Grant S
authors.initials: GS
authors.lastname: Stewart
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Byrd
authors.forename: Thomas
authors.initials: T
authors.lastname: Wechsler
authors.forename: Edward S
authors.initials: ES
authors.lastname: Miller
authors.forename: Aarn
authors.initials: A
authors.lastname: Huissoon
authors.forename: Mark T
authors.initials: MT
authors.lastname: Drayson
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: A Malcolm R
authors.initials: AM
authors.lastname: Taylor
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D005347:Fibroblasts / Q000473:pathology / Q000528:radiation effects; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000528:radiation effects; D007153:Immunologic Deficiency Syndromes / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000528:radiation effects; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011995:Recombination, Genetic / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000528:radiation effects; D015534:Trans-Activators / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D045643:DNA Repair Enzymes