Docking of a Specialized PIP Box onto Chromatin-Bound PCNA Creates a Degron for the Ubiquitin Ligase CRL4Cdt2

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Abstract

Substrates of the E3 ubiquitin ligase CRL4Cdt2, including Cdt1 and p21, contain a PCNA-binding motif called a PIP box. Upon binding of the PIP box to PCNA on chromatin, CRL4Cdt2 is recruited and the substrate is ubiquitylated. Importantly, a PIP box cannot be sufficient for destruction, as most PIP box proteins are stable. Using Xenopus egg extracts, we identify two sequence elements in CRL4Cdt2 substrates that promote their proteolysis: a specialized PIP box that confers exceptionally efficient PCNA binding and a basic amino acid 4 residues downstream of the PIP box, which recruits CRL4Cdt2 to the substrate-PCNA complex. We also identify two mechanisms that couple CRL4Cdt2-dependent proteolysis to the chromatin-bound form of PCNA, ensuring that this proteolysis pathway is active only in S phase or after DNA damage. Thus, CRL4Cdt2 recognizes an unusual degron, which is assembled specifically on chromatin via the binding of a specialized PIP box to PCNA. © 2009 Elsevier Inc. All rights reserved.

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Havens, C. G., & Walter, J. C. (2009). Docking of a Specialized PIP Box onto Chromatin-Bound PCNA Creates a Degron for the Ubiquitin Ligase CRL4Cdt2. Molecular Cell, 35(1), 93–104. https://doi.org/10.1016/j.molcel.2009.05.012

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