p15PAF Is an Rb/E2F-Regulated S-Phase Protein Essential for DNA Synthesis and Cell Cycle Progression

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.