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

Abstract

The p15PAF/KIAA0101 protein is a proliferating cell nuclear antigen (PCNA)-associated protein overexpressed in multiple types of cancer. Attenuation of p15PAF expression leads to modifications in the DNA repair process, rendering cells more sensitive to ultraviolet-induced cell death. In this study, we identified that p15PAF expression peaks during the S phase of the cell cycle. We observed that p15PAF knockdown markedly inhibited cell proliferation, S-phase progression, and DNA synthesis. Depletion of p15PAF resulted in p21 upregulation, especially chromatin-bound p21. We further identified that the p15PAF promoter contains 3 E2F-binding motifs. Loss of Rb-mediated transcriptional repression resulted in upregulated p15PAF expression. Binding of E2F4 and E2F6 to the p15PAF promoter caused transcriptional repression. Overall, these results indicate that p15PAF is tightly regulated by the Rb/E2F complex. Loss of Rb/E2F-mediated repression during the G1/S transition phase leads to p15PAF upregulation, which facilitates DNA synthesis and S-phase progression. © 2013 Chang et al.