Homozygous deficiency of ubiquitin ligase RNF168 defines a radiosensitivity syndrome mimicking ataxia-telangiectasia

Jiri Bartek (1) , Sue Devgan (1) , Carsten Doil (1) , Kotoka Nakamura (1) , Kelly Pettijohn (1) , Shareef Nahas (1) , Claudia Lukas (1) , Jiri Lukas (1) , Richard Gatti (1)

1 Centre for Genotoxic Stress Research

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 pathway of several E3 ubiquitin ligases that perform sequential ubiquitylations on damaged chromosomes, 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 (A-T). The mutation eliminated both of RNF168's ubiquitin-binding motifs, thus blocking 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 radiosensitivity. 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.

Mots clés: DNA damage response; RNF168 and BRCA1 ubiquitin ligases; ionizing radiation 53BP1 foci; ataxia-telangiectasia mimicking syndrome; alpha fetoprotein

Jiri Bartek, Sue Devgan, Carsten Doil, Kotoka Nakamura, Kelly Pettijohn, et al.. Homozygous deficiency of ubiquitin ligase RNF168 defines a radiosensitivity syndrome mimicking ataxia-telangiectasia. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.18⟩. ⟨hal-00621616⟩