Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome

Bohgaki, Toshiyuki; Bohgaki, Miyuki; Cardoso, Renato; Panier, Stephanie; Zeegers, Dimphy; Li, Li; Stewart, Grant S.; Sánchez, Otto; Hande, M. Prakash; Durocher, Daniel; Hakem, Anne; Hakem, Razqallah

doi:10.1371/journal.pgen.1001381

Cited by 75 publications

(71 citation statements)

References 77 publications

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“…We show that similar to the effect of null or hypomorphic mutations of genes involved in DSB signaling, such as H2Ax, 24 Mdc1, 25 Rnf8, 38 Rnf168, 39 Rnf4 hypomorphic mice are growth retarded and radiosensitive. In addition, we observed increased cell death and a reduced number of spermatocytes in the seminiferous tubules of these mice.…”

Section: Discussionmentioning

confidence: 60%

“…In addition, we observed increased cell death and a reduced number of spermatocytes in the seminiferous tubules of these mice. This meiotic defect is also reminiscent of loss of DDR proteins such as H2Ax, 24 Mdc1, 25 Rnf8, 38 and Rnf168, 39 and can be explained by the observation that Spo-11-mediated generation of DSBs and their repair by HR are required for proper meiosis. 37 Together, these data establish an important genetic link between Rnf4 and the DDR in mammalian cells.…”

Section: Discussionmentioning

confidence: 99%

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RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiationinduced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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“…In mice, loss of RNF168 causes immunodeficiency and radiosensitivity as well as increased genomic instability. Mechanistically, inactivation of RNF168 impairs long‐range V(D)J recombination in mouse thymocytes 51. A similar phenotype was shown in 53BP1‐deficient mice, which are radiosensitive and immunodeficient 52.…”

Section: Genes and Diseases Associated With Defective Recombination Imentioning

confidence: 62%

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

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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“…In contrast, deficiency of Rnf168 in mouse embryonic fibroblasts (MEFs) completely abolishes 53bp1 recruitment to DSB sites (12). Similar to 53bp1 −/− mice, but in contrast to H2a.x −/− mice (13), young Rnf168 −/− males are fertile (12). These data suggest that, in addition to its role in DSB signaling downstream of the H2A.…”

mentioning

confidence: 95%

“…Although H2A.X, MDC1, and RNF8 are important for the retention of 53BP1 at these DSBs, its initial and transient recruitment to DNA breaks still occurs in their absence (8)(9)(10)(11). In contrast, deficiency of Rnf168 in mouse embryonic fibroblasts (MEFs) completely abolishes 53bp1 recruitment to DSB sites (12). Similar to 53bp1 −/− mice, but in contrast to H2a.x −/− mice (13), young Rnf168 −/− males are fertile (12).…”

mentioning

confidence: 99%

RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks

Bohgaki

Ghamrasni

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Defective signaling or repair of DNA double-strand breaks has been associated with developmental defects and human diseases. The E3 ligase RING finger 168 (RNF168), mutated in the human radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome, was shown to ubiquitylate H2A-type histones, and this ubiquitylation was proposed to facilitate the recruitment of p53-binding protein 1 (53BP1) to the sites of DNA double-strand breaks. In contrast to more upstream proteins signaling DNA double-strand breaks (e.g., RNF8), deficiency of RNF168 fully prevents both the initial recruitment to and retention of 53BP1 at sites of DNA damage; however, the mechanism for this difference has remained unclear. Here, we identify mechanisms that regulate 53BP1 recruitment to the sites of DNA double-strand breaks and provide evidence that RNF168 plays a central role in the regulation of 53BP1 functions. RNF168 mediates K63-linked ubiquitylation of 53BP1 which is required for the initial recruitment of 53BP1 to sites of DNA double-strand breaks and for its function in DNA damage repair, checkpoint activation, and genomic integrity. Our findings highlight the multistep roles of RNF168 in signaling DNA damage.ubiquitin | G2/M checkpoint | HR repair pathways | NHEJ repair pathway T he DNA-damage response (DDR) is critical for genomic integrity (1) and is regulated by posttranslational modifications (PTMs) such as ubiquitylation of histones by the E3 ligases RING finger 8 (RNF8) and RING finger 168 (RNF168). Other PTMs important for DDR include dimethylation of histone H4 (H4K20me2), which allows p53-binding protein 1 (53BP1), a key mediator of DDR, to interact with chromatin.Mutations of RNF168 have been associated with the human radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome, (2-4). RNF168 has an N-terminal RING finger domain, three ubiquitin (Ub)-binding domains (UBDs); two motif interacting with Ub (MIU) domains; and one Ub interacting motif (UIM)-and MIU-related (UMI) UBD (3,5,6). Current data support RNF168 function in DNA double-strand break (DSB) signaling downstream of H2A.X, mediator of DNA damage checkpoint 1 (MDC1), and RNF8 and indicate its requirement for 53BP1 recruitment to DSB sites (3, 5). Through its UBDs, RNF168 recognizes RNF8 ubiquitylated non-nucleosomal protein(s) at DSB-flanking sites, leading to its recruitment at these sites of DNA damage (7). With the Ubconjugating enzyme UBC13, RNF168 initiates ubiquitylation of lysine (K) 13 or 15 of histones H2A and H2A.X, leading to the recruitment of DDR proteins, including 53BP1, to DSBs. Although H2A.X, MDC1, and RNF8 are important for the retention of 53BP1 at these DSBs, its initial and transient recruitment to DNA breaks still occurs in their absence (8-11). In contrast, deficiency of Rnf168 in mouse embryonic fibroblasts (MEFs) completely abolishes 53bp1 recruitment to DSB sites (12). Similar to 53bp1 −/− mice, but in contrast to H2a.x −/− mice (13), young Rnf168 −/− males are ferti...

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Genomic Instability, Defective Spermatogenesis, Immunodeficiency, and Cancer in a Mouse Model of the RIDDLE Syndrome

Cited by 75 publications

References 77 publications

RNF4 is required for DNA double-strand break repair in vivo

RNF4 is required for DNA double-strand break repair in vivo

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

RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks

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