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 showed that the elevated and persistent levels of p53 displayed by CS cells are due to the insufficient ubiquitination of the p53 protein. We further demonstrated that CSA and CSB proteins associate in a unique complex with p53 and Mdm2; this interaction greatly stimulates the ubiquitination of p53 in an Mdm2-dependent manner. Tandem affinity purification and immunoprecipitations combined with mass spectrometry studies indicate that CSA and CSB associate within a Cullin Ring Ubiquitin Ligase complex responsible, under certain circumstances, for p53 ubiquitination. 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.
Unit of Molecular Genetics of Aging, DEB, University of Tuscia, Viterbo, Italy.
Paolo
P
Latini
Mattia
M
Frontini
Manuela
M
Caputo
Juraj
J
Gregan
Lubos
L
Cipak
Silvia
S
Filippi
Vivek
V
Kumar
Renier
R
Vélez-Cruz
Miria
M
Stefanini
Luca
L
Proietti-De-Santis
D003057:Cockayne Syndrome / Q000235:genetics* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D000075223:Poly-ADP-Ribose Binding Proteins; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
C095472:ERCC8 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes