DNA replication requires the PCNA sliding clamp, which encircles the DNA and anchors polymerases and other DNA-editing enzymes. PCNA also interacts with regulatory proteins like the oncogenic p15PAF (aka p15), which facilitates the switch from replicative to translesion synthesis polymerases in response to DNA damage. This protein is over-expressed in different types of cancer with levels that correlate with poor prognosis. p15 is an intrinsically disordered protein that threads through the PCNA ring. The p15 central region binds the PCNA front face while the N- and C-termini remain disordered at opposite faces of the ring. Fast sliding implies weak, transient PCNA-DNA interactions, and p15 binding to the inner side of the ring modulates sliding. p15 also interacts with DNA through its N-terminal region, and we propose that p15 regulates the PCNA sliding velocity on the DNA. Post-translational modifications may further regulate this process as p15 is partially ubiquitinated inside cells.
Model of an ensemble with 10 different p15 conformers bound to the PCNA ring illustrating the disordered state of the p15 tails and the ordered central region (as seen by X-ray crystallography)