Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 6, Pages 3692-3706Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1400
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Funding
- Ligue Nationale Contre le Cancer
- Ministry of Higher Education and Research [MNERT grant]
- Fondation pour la Recherche Medicale (FRM)
- Fondation ARC pour la Recherche sur le Cancer
- Centre National de la Recherche Scientifique (CNRS)
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Proliferating cell nuclear antigen (PCNA) is a well-known scaffold for many DNA replication and repair proteins, but how the switch between partners is regulated is currently unclear. Interaction with PCNA occurs via a domain known as a PCNA-Interacting Protein motif (PIP box). More recently, an additional specialized PIP box has been described, the ' PIP degron ', that targets PCNA-interacting proteins for proteasomal degradation via the E3 ubiquitin ligase CRL4(Cdt2). Here we provide evidence that CRL4(Cdt2)-dependent degradation of PIP degron proteins plays a role in the switch of PCNA partners during the DNA damage response by facilitating accumulation of translesion synthesis DNA polymerases into nuclear foci. We show that expression of a nondegradable PIP degron (Cdt1) impairs both Pol eta and Pol kappa focus formation on ultraviolet irradiation and reduces cell viability, while canonical PIP box-containing proteins have no effect. Furthermore, we identify PIP degron-containing peptides from several substrates of CRL4(Cdt2) as efficient inhibitors of Pol eta foci formation. By site-directed mutagenesis we show that inhibition depends on a conserved threonine residue that confers high affinity for PCNA-binding. Altogether these findings reveal an important regulative role for the CRL4(Cdt2) pathway in the switch of PCNA partners on DNA damage.
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