SCFFbxw15 Mediates Histone Acetyltransferase Binding to Origin Recognition Complex (HBO1) Ubiquitin-Proteasomal Degradation to Regulate Cell Proliferation *

Histone acetyltransferase binding to origin recognition complex (HBO1) plays a crucial role in DNA replication licensing and cell proliferation, yet its molecular regulation in cells is relatively unknown. Here an uncharacterized protein, Fbxw15, directly interacts with HBO1, a labile protein ( t ½ = ∼3 h), to mediate its ubiquitination (Lys 338 ) and degradation in the cytoplasm. Fbxw15-mediated HBO1 depletion required mitogen-activated protein kinase 1 (Mek1), which was sufficient to trigger HBO1 phosphorylation and degradation in cells. Mek1 ability to produce HBO1 degradation was blocked by Fbxw15 silencing. Lipopolysaccharide induced HBO1 degradation, an effect abrogated by Fbxw15 or Mek1 cellular depletion. Modulation of Fbxw15 levels was able to differentially regulate histone H3K14 acetylation and cellular proliferation by altering HBO1 levels. These studies authenticate Fbxw15 as a ubiquitin E3 ligase subunit that mediates endotoxin-induced HBO1 depletion in cells, thereby controlling cell replicative capacity. Background: HBO1 is a crucial enzyme needed for DNA replication, yet mechanisms for its disposal are unknown. Results: A ubiquitin E3 ligase subunit, Fbxw15, mediates HBO1 degradation in concert with Mek1 kinase after endotoxin exposure. Conclusion: Fbxw15 targets HBO1 for its site-specific ubiquitination and degradation leading to reduced histone acetylation and cellular proliferation. Significance: The molecular control of HBO1 protein levels may impact fundamental cellular processes during inflammation.