p15 ^PAF Is an Rb/E2F-Regulated S-Phase Protein Essential for DNA Synthesis and Cell Cycle Progression

Abstract

The p15 ^PAF/KIAA0101 protein is a proliferating cell nuclear antigen (PCNA)-associated protein overexpressed in multiple types of cancer. Attenuation of p15 ^PAF expression leads to modifications in the DNA repair process, rendering cells more sensitive to ultraviolet-induced cell death. In this study, we identified that p15 ^PAF expression peaks during the S phase of the cell cycle. We observed that p15 ^PAF knockdown markedly inhibited cell proliferation, S-phase progression, and DNA synthesis. Depletion of p15 ^PAF resulted in p21 upregulation, especially chromatin-bound p21. We further identified that the p15 ^PAF promoter contains 3 E2F-binding motifs. Loss of Rb-mediated transcriptional repression resulted in upregulated p15 ^PAF expression. Binding of E2F4 and E2F6 to the p15 ^PAF promoter caused transcriptional repression. Overall, these results indicate that p15 ^PAF is tightly regulated by the Rb/E2F complex. Loss of Rb/E2F-mediated repression during the G1/S transition phase leads to p15 ^PAF upregulation, which facilitates DNA synthesis and S-phase progression.