Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia

• Published in: Cell death and differentiation 2011-09, Vol.18 (9), p.1500-1506
• Main Authors: Devgan, S S, Sanal, O, Doil, C, Nakamura, K, Nahas, S A, Pettijohn, K, Bartek, J, Lukas, C, Lukas, J, Gatti, R A
• Format: Article
• Language: English
• Subjects: 631/208/737; 631/337/1427/2122; 692/699/317; Adolescent; Aging; Apoptosis; Ataxia telangiectasia; Ataxia Telangiectasia - diagnosis; Ataxia Telangiectasia - genetics; Ataxia Telangiectasia - metabolism; Ataxia Telangiectasia - physiopathology; Biochemistry; Biomedical and Life Sciences; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Cancer; Cell Biology; Cell Cycle Analysis; Chromatin; Chromosomes; Codon, Nonsense; Diagnosis, Differential; Differential diagnosis; DNA damage; Double-strand break repair; genomics; Growth Disorders - genetics; Growth Disorders - physiopathology; Homozygote; Humans; Immunodeficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Life Sciences; Lung; Male; Microencephaly; Mimicry; Neurodegeneration; Nonsense mutation; Original Paper; Radiation Tolerance - genetics; Radiosensitivity; Stem Cells; Syndrome; Tumor suppressor genes; Tumor Suppressor p53-Binding Protein 1; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.18

Maintaining genomic integrity is critical to avoid life-threatening disorders, such as premature aging, neurodegeneration and cancer. A multiprotein cascade operates at sites of DNA double-strand breaks (DSBs) to recognize, signal and repair damage. RNF168 (ring-finger nuclear factor) contributes to this emerging pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, chromatin modifications essential for aggregation of repair complexes at the DSB sites. Here, we report the clinical and cellular phenotypes associated with a newly identified homozygous nonsense mutation in the RNF168 gene of a patient with a syndrome mimicking ataxia-telangiectasia. The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking progression of the ubiquitylation cascade and retention of repair proteins including tumor suppressors 53BP1 and BRCA1 at DSB sites, consistent with the observed defective DNA damage checkpoints/repair and pronounced radiosensitivity. Rapid screening for RNF168 pathway deficiency was achieved by scoring patients' lymphoblastoid cells for irradiation-induced nuclear foci containing 53BP1, a robust assay we propose for future diagnostic applications. The formation of radiation-induced DSB repair foci was rescued by ectopic expression of wild-type RNF168 in patient's cells, further causally linking the RNF168 mutation with the pathology. Clinically, this novel syndrome featured ataxia, telangiectasia, elevated alphafetoprotein, immunodeficiency, microcephaly and pulmonary failure and has implications for the differential diagnosis of autosomal recessive ataxias.