CSA and CSB proteins interact with p53 and regulate its Mdm2-dependent ubiquitination

Mutations in Cockayne syndrome (CS) A and B genes (CSA and CSB) result in a rare genetic disease that affects the development and homeostasis of a wide range of tissues and organs. We previously correlated the degenerative phenotype of patients to the enhanced apoptotic response, exhibited by CS cells, which is associated with the exceptional induction of p53 protein upon a variety of stress stimuli. Here we show that the elevated and persistent levels of p53 displayed by CS cells are due to the insufficient ubiquitination of p53. We further demonstrate that CSA and CSB proteins are part of a Cullin Ring Ubiquitin Ligase complex with p53 and Mdm2; this interaction greatly stimulates the ubiquitination of p53 in an Mdm2-dependent manner. Finally, we have found that p53 binds to the CSB promoter and transcriptionally controls the expression of csb gene allowing the establishment of a negative feedback loop that causes p53 to return at basal levels. This study identifies CSA and CSB as the key elements of a regulatory mechanism that equilibrate beneficial and detrimental effects of p53 activity upon cellular stress. The deregulation of p53, in absence of either of the CS proteins, can potentially explain the early onset degeneration of tissues and organs observed in CS patients.