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 endjoining 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 doublestrand break-repair protein that functions upstream of 53BP1 and contributes to the normal development of the human immune system. DNA repair ͉ cell cycle checkpoint ͉ radiosensitivity ͉ BRCA1

The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination

“…Our data suggest that RNF8/RNF168 have an incomplete effect on CSR; however, our shRNA constructs cannot completely deplete these factors. The finding that serum IgG is reduced by ∼10-fold in a patient with RIDDLE syndrome deficient in RNF168 (18) suggests that complete ablation of RNF8 or RNF168 would produce a pronounced phenotype.…”

“…Once at the break, RNF8 mediates the monoubiquitination of H2A-type histones, among other potential proteins. Monoubiquitinated H2A-type histones subsequently signal the recruitment of another E3 ubiquitin ligase, RNF168 (16, 17), a mutation of which was recently reported in an immunodeficient and radiosensitive patient with RIDDLE syndrome (16,18). RNF168 protects and amplifies the RNF8-mediated ubiquitination by catalyzing the addition of K63-linked polyubiquitin chains at DNA damage sites (16,17).…”

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

“…Cells from the RIDDLE patient lack the ability to recruit the NHEJ‐promoting protein 53BP1 to sites of DSBs, where it localizes immediately after DNA damage and is involved in checkpoint control. Such cells exhibit hypersensitivity to ionizing radiation, cell cycle defects and impaired end‐joining during CSR in B cells 48, 49. A homozygous RNF168 mutation was also reported in a patient with a syndrome mimicking ataxia telangiectasia (AT) 50.…”

H1 provides the missing link

“…Key to the formation of these DSBassociated ubiquitin adducts are the E3 ubiquitin ligases RNF8 and RNF168 [2][3][4][5][6][7]. RNF8 and RNF168 docking at DSBs follow a hierarchical sequence, and while the pair of E3 enzymes have been envisaged to, in concerted efforts, assemble DNA repair factors by ubiquitylating core histone proteins, the molecular basis that underlies their strict order of appearance at DSBs has remained elusive.RNF168, also known as the RIDDLE syndrome protein, was first described in a patient with radiosensitivity and immunodeficiency, clinical manifestations that are characteristic of defective responses to DSBs [6,8]. In addition to possessing a signature RING domain, the E3 ubiquitin ligase RNF168 also harbors two clusters of protein-interacting motifs (the authors referred to these as UDM1 and UDM2; see Figure 1) that supported its accrual at DNA damage sites [6,7,9,10].…”

“…RNF168, also known as the RIDDLE syndrome protein, was first described in a patient with radiosensitivity and immunodeficiency, clinical manifestations that are characteristic of defective responses to DSBs [6,8]. In addition to possessing a signature RING domain, the E3 ubiquitin ligase RNF168 also harbors two clusters of protein-interacting motifs (the authors referred to these as UDM1 and UDM2; see Figure 1) that supported its accrual at DNA damage sites [6,7,9,10].…”