Abstract
The proliferating cell nuclear antigen (PCNA) is an essential protein for DNA replication and damage repair. How its function is controlled remains an important question. Here, we show that the chromatin-bound PCNA protein is phosphorylated on Tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of EGF receptor (EGFR) in the nucleus. Phosphorylation on Tyr 211 by EGFR stabilizes chromatin-bound PCNA protein and associated functions. Consistently, increased PCNA Tyr 211 phosphorylation coincides with pronounced cell proliferation, and is better correlated with poor survival of breast cancer patients, as well as nuclear EGFR in tumours, than is the total PCNA level. These results identify a novel nuclear mechanism linking tyrosine kinase receptor function with the regulation of the PCNA sliding clamp.
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Acknowledgements
The anti-phospho-Tyr 211 antibody was generated by Bethyl Laboratories, Inc. as a collaboration. We also thank S. Dent, M. Van Dyke and D. Yu for helpful discussions and comments. This study was supported, in part, by the NIH RO1 109311 and NIH PO1 099031 grants, the National Breast Cancer Foundation, Inc. (to M.-C. H.), and the Cancer Center support grant CA16672.
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E.W.M is currently an employee of Bethyl Laboratories, Inc. (Montgomery, TX), which has a commerical interest in the antibodies against PCNA and phospho-PCNA. E.W.M. collaborated with the Hung group to develop these antibodies.
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Wang, SC., Nakajima, Y., Yu, YL. et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 8, 1359–1368 (2006). https://doi.org/10.1038/ncb1501
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DOI: https://doi.org/10.1038/ncb1501
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