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Title: p15PAF binding to PCNA modulates the DNA sliding surface.
Authors: De March, M
Barrera-Vilarmau, S
Crespan, E
Mentegari, E
Merino, N
Gonzalez-Magaña, A
Romano-Moreno, M
Maga, G
Crehuet, R
Onesti, S
Blanco, FJ
De Biasio, A
First Published: 8-Aug-2018
Publisher: Oxford University Press (OUP)
Citation: Nucleic Acids Research, 2018, 46(18), pp. 9816–9828
Abstract: p15PAF is an oncogenic intrinsically disordered protein that regulates DNA replication and lesion bypass by interacting with the human sliding clamp PCNA. In the absence of DNA, p15PAF traverses the PCNA ring via an extended PIP-box that contacts the sliding surface. Here, we probed the atomic-scale structure of p15PAF-PCNA-DNA ternary complexes. Crystallography and MD simulations show that, when p15PAF occupies two subunits of the PCNA homotrimer, DNA within the ring channel binds the unoccupied subunit. The structure of PCNA-bound p15PAF in the absence and presence of DNA is invariant, and solution NMR confirms that DNA does not displace p15PAF from the ring wall. Thus, p15PAF reduces the available sliding surfaces of PCNA, and may function as a belt that fastens the DNA to the clamp during synthesis by the replicative polymerase (pol δ). This constraint, however, may need to be released for efficient DNA lesion bypass by the translesion synthesis polymerase (pol η). Accordingly, our biochemical data show that p15PAF impairs primer synthesis by pol η-PCNA holoenzyme against both damaged and normal DNA templates. In light of our findings, we discuss the possible mechanistic roles of p15PAF in DNA replication and suppression of DNA lesion bypass.
DOI Link: 10.1093/nar/gky723
eISSN: 1362-4962
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Atomic coordinates of p1550–77–PCNA–DNA and p1541–72–PCNA complexes have been deposited in the Protein Databank under the accession codes 6EHT and 6GWS, respectively. Assignments of backbone amide NMR resonances of human PCNA bound to p1550–77 and DNA are deposited in the Biological Magnetic Resonance database BMRB under accession code 27558. Supplementary Data are available at NAR Online
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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