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A Novel Mechanism for Regulating the Activity of Proliferating Cell Nuclear Antigen by a Small Protein



Zvi Kelman, Richard Y. Huang, Zhuo Li, Jerard Hurwitz, Santangelo J. Thomas, Travis H. Hileman, Yopp C. Daniel, Jeffrey W. Hudgens


Chromosomal DNA replication requires the regulated activity of large number of proteins and complexes. Proliferating cell nuclear antigen (PCNA) protein forms a homotrimeric ring that associates with, and regulates the activity of, many proteins participating in DNA metabolic processes and cell cycle progression in archaea and eukarya. A previously uncharacterized small protein, encoded by TK0808 in the archaeon Thermococcus kodakarensis, was shown to stably interact with PCNA protein in vivo. It is shown here that the protein, designated Thermococcales inhibitor of PCNA (TIP), binds to PCNA in vivo and in vitro and results in the inhibition of PCNA-dependent activities. Using Hydrogen/Deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis, the interacting regions of PCNA and TIP have been identified. While most proteins that interact with PCNA do so via a PCNA-interacting peptide (PIP) motif that interacts with the inter domain connecting loop (IDCL) on PCNA, TIP neither contains the canonical PIP motif nor interacts with PCNA via the IDCL. These findings suggest a new mechanism for PCNA binding and for regulation of PCNA-dependent activities.
Nucleic Acids Research


archaea, DNA replication, H/D exchange, PCNA


Kelman, Z. , Huang, R. , Li, Z. , Hurwitz, J. , Thomas, S. , Hileman, T. , Daniel, Y. and Hudgens, J. (2014), A Novel Mechanism for Regulating the Activity of Proliferating Cell Nuclear Antigen by a Small Protein, Nucleic Acids Research, [online],, (Accessed April 21, 2024)
Created March 9, 2014, Updated January 4, 2022