Abstract
The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic disorders that show increased genomic instability, cancer predisposition, hypersensitivity to mitomycin C and gamma-irradiation, shortened telomeres, and cell cycle defects. The protein mutated in the premature aging disease known as the Werner syndrome is designated WRN and is a member of the RecQ helicase family. The Nbs1 protein is mutated in Nijmegen breakage syndrome individuals and is part of the mammalian Mre11 complex together with the Mre11 and Rad50 proteins. Here, we show that WRN associates with the Mre11 complex via binding to Nbs1 in vitro and in vivo. In response to gamma-irradiation or mitomycin C, WRN leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm. We detect an increased association between WRN and the Mre11 complex after cellular exposure to gamma-irradiation. Small interfering RNA and complementation experiments demonstrated convergence of WRN and Nbs1 in response to gamma-irradiation or mitomycin C. Nbs1 is required for the Mre11 complex promotion of WRN helicase activity. Taken together, these results demonstrate a functional link between the two genetic diseases with partially overlapping phenotypes in a pathway that responds to DNA double strand breaks and interstrand cross-links.
Highlights
The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic disorders that show increased genomic instability, cancer predisposition, hypersensitivity to mitomycin C and ␥-irradiation, shortened telomeres, and cell cycle defects
When anti-Nbs1, anti-Mre11, and anti-Rad50 immunoprecipitates were analyzed by immunoblotting with an anti-WRN antibody in reciprocal experiments, the results confirmed the association between WRN and the Mre11 complex (Fig. 1B, top panel)
Consistent with an earlier report showing that Mre11 was mis-located to the cytoplasm in the W1799 Nijmegen breakage syndrome (NBS) fibroblasts by immunostaining [4], we detected a significant portion of the Mre11 and Rad50 proteins in the cytoplasmic fraction from the NBS, but not in normal fibroblasts (Fig. 1E)
Summary
The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic disorders that show increased genomic instability, cancer predisposition, hypersensitivity to mitomycin C and ␥-irradiation, shortened telomeres, and cell cycle defects. When anti-Nbs1, anti-Mre11, and anti-Rad50 immunoprecipitates were analyzed by immunoblotting with an anti-WRN antibody in reciprocal experiments, the results confirmed the association between WRN and the Mre11 complex (Fig. 1B, top panel).
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