Damaged DNA binding proteins (DDBs) play a critical role in the initial recognition of UV-damaged DNA and mediate recruitment of nucleotide excision repair factors. Previous studies identified DDB2 as a target of the CUL-4A ubiquitin ligase. However, the biochemical mechanism governing DDB proteolysis and its underlying physiological function in the removal of UV-induced DNA damage are largely unknown. Here, we report that the c-Abl nonreceptor tyrosine kinase negatively regulates the repair of UV-induced photolesions on genomic DNA. Biochemical studies revealed that c-Abl promotes CUL-4A-mediated DDB ubiquitination and degradation in a manner that does not require its tyrosine kinase activity both under normal growth conditions and following UV irradiation. Moreover, c-Abl activates DDB degradation in part by alleviating the inhibitory effect of CAND1/TIP120A on CUL-4A. These results revealed a kinase-independent function of c-Abl in a ubiquitin-proteolytic pathway that regulates the damage recognition step of nucleotide excision repair. © 2006 Elsevier Inc. All rights reserved.
Chen, X., Zhang, J., Lee, J., Lin, P. S., Ford, J. M., Zheng, N., & Zhou, P. (2006). A Kinase-Independent Function of c-Abl in Promoting Proteolytic Destruction of Damaged DNA Binding Proteins. Molecular Cell, 22(4), 489–499. https://doi.org/10.1016/j.molcel.2006.04.021