Role of Claspin in regulating nucleotide excision repair Free

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We have recently found that the human mediator of the replication checkpoint response and DNA damage sensor protein, Claspin, physically interacts with nucleotide excision repair (NER) proteins DDB1, DDB2 and XPC. We also demonstrated that the presence of Claspin is required for UV-induced degradation of DDB2 and its co-localization to DNA lesions, but not for the repair of DNA lesions. These findings demonstrate both physical and functional interactions between the DNA damage signaling pathway and NER. Results presented here now further indicate that the UV-dependent transcriptional induction of DDB2 that precedes its proteolysis is affected in Claspin knock-down cells. This finding indicates an additional role of Claspin in signaling the DNA damage-dependent activation of p53, which is known to transcriptionally induce expression of the NER factors DDB2 and XPC upon UV-induced DNA damage. Data will be presented that examine the role of Claspin in the total turnover of the two factors DDB2 and XPC upon UV irradiation. In addition investigations are undertaken that aim to clarify the function of Claspin and other DNA damage signaling factors in the UV-related crosstalk events in eukaryotic NER pathway. (Supported by NIH grants ES002388, ES12991 and CA93413).