The role of the Cockayne syndrome protein

National Institute On Aging

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Abstract

Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA repair and transcription. In CS cells, there are deficiencies in the repair of oxidative DNA damage in the nuclear and mitochondrial DNA, and this may be a major underlying cause of the disease. Previously, we demonstrated that the CSB protein interacts with PARP1, a protein involved in the early steps of DNA single-strand break repair, and that these two proteins cooperate in the cellular responses to oxidative stress. CSB is a substrate for PARP-1 ribosylation and it is likely that these two proteins function together in the process of base excision. Our results indicate that the CSB protein plays an important role in the repair of oxidative DNA damage and that accumulation of unrepaired lesions, particular in target tissues, like the brain, may be relevant for the CS pathology, which is characterized by severe early onset neurodegeneration. The clinical feature of mice carrying a mutation in CSB involves hearing loss, microglial activation, cachexia, and are mild compared to the catastrophic disease phenotype of CS in human patients. Our recent studies reveal novel complex features of the CSB mouse model, including elevated metabolic rate and altered autophagy. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated, presumably as a result of defects in the recruitment of P62 and mitochondrial ubiquitination. CSB-deficient cells show increased free radical production and an accumulation of damaged mitochondria.