title: Proliferating cell nuclear antigen (PCNA)-associated KIAA0101/PAF15 protein is a cell cycle-regulated anaphase-promoting complex/cyclosome substrate.
abstract: The anaphase-promoting complex/cyclosome (APC/C) is a cell cycle-regulated E3 ubiquitin ligase that controls the degradation of substrate proteins at mitotic exit and throughout the G1 phase. We have identified an APC/C substrate and cell cycle-regulated protein, KIAA0101/PAF15. PAF15 protein levels peak in the G2/M phase of the cell cycle and drop rapidly at mitotic exit in an APC/C- and KEN-box-dependent fashion. PAF15 associates with proliferating cell nuclear antigen (PCNA), and depletion of PAF15 decreases the number of cells in S phase, suggesting a role for it in cell cycle regulation. Following irradiation, PAF15 colocalized with γH2AX foci at sites of DNA damage through its interaction with PCNA. Finally, PAF15 depletion led to an increase in homologous recombination-mediated DNA repair, and overexpression caused sensitivity to UV-induced DNA damage. We conclude that PAF15 is an APC/C-regulated protein involved in both cell cycle progression and the DNA damage response.
authors.affiliation: Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Emanuele
authors.forename: Alberto
authors.initials: A
authors.lastname: Ciccia
authors.forename: Andrew E H
authors.initials: AE
authors.lastname: Elia
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005434:Flow Cytometry; D016195:G2 Phase; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D011995:Recombination, Genetic; D016196:S Phase; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C425208:PCLAF protein, human; D018809:Proliferating Cell Nuclear Antigen; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome