Exact values: vs = 4.10×10-6; vs = 2.53×10-6. anaphase and perinuclear silencing of the gene in the following G1 phase. Hos3-dependent coordination of both events restrains Start in daughter but not in mother cells. We propose that deacetylation modulates transport-dependent and -independent functions of NPCs, leading to differential cell cycle progression in mother and daughter cells. Similar mechanisms might regulate NPC functions in specific cell types and/or cell cycle stages in multicellular organisms. Introduction Asymmetric cell division is a conserved mechanism that generates diversity in cell populations. Asymmetric divisions are found in both unicellular organisms and metazoans, where they play a major role in stem cell self-renewal and tissue homeostasis during development 1,2. During asymmetric division, unequal partitioning of cell fate determinants between the new cells leads to their different identities. We have investigated how the acquisition of cell Pomalidomide-C2-NH2 hydrochloride identity is controlled by nuclear pore complexes (NPCs) during asymmetric cell division. NPCs are macromolecular assemblies composed of approximately 30 nucleoporins forming channels across the nuclear envelope (NE) to mediate transport between the nucleus and the cytoplasm 3C5. Nucleo-cytoplasmic transport of proteins and RNA is intimately tied to the regulation of gene expression and cell fate determination 6,7. Additionally, the NE and nucleoporins associated with the nuclear basket of NPCs can directly interact with the nuclear genome to regulate gene expression and thus affect cell differentiation [reviewed in 7C10]. In particular, Pomalidomide-C2-NH2 hydrochloride the nuclear periphery is a transcriptionally repressive environment in yeast and metazoans 11C14, and gene repositioning from the nuclear interior to the periphery can result in silencing 15,16. The composition of both the NE and NPCs, and their interactions with the genome, are known to diverge during development 17C20. However, how differences in perinuclear function are established during development, and in particular during asymmetric cell divisions, remains unclear. Budding yeast divide asymmetrically, giving rise to mother and daughter cells of different size, age, transcriptional profiles and cell cycle programs 21C23. Notably, commitment to a new division cycle is regulated asymmetrically in or cyclin E, respectively) controlling the start of S phase. SBF or E2F are inhibited in G1 by a transcriptional repressor: Whi5 in yeast, and its homolog the Rb tumour suppressor in mammals. In yeast, a key event driving Pomalidomide-C2-NH2 hydrochloride the G1/S transition is the dilution of Whi5 activity by cell growth, whereby the volume increase in daughter cells during G1 lowers the concentration of Whi5 below a critical threshold 27. Vegfa This allows Cyclin-dependent kinase (Cdk) complexes to inactivate Whi5, which is then evicted from the nucleus 28,29. Interestingly, the G1 concentration of Whi5 is higher in daughter cells than in mother cells Pomalidomide-C2-NH2 hydrochloride 27,30. The mechanism establishing this asymmetry is not known. Here, we reveal that cell cycle entry in budding yeast daughters is inhibited by association of the lysine deacetylase Hos3 with daughter-cell NPCs. We identify the mechanism recruiting Hos3 to NPCs during mitosis. Further, we demonstrate that Hos3-mediated NPC deacetylation establishes asymmetric segregation of the Whi5 transcriptional repressor and perinuclear silencing of the G1/S cyclin gene in daughters, which together contribute to inhibit Start. Thus, cell-specific deacetylation of NPCs directs differences in cell identity during asymmetric division. Results Hos3 inhibits cell cycle entry in daughter cells Commitment to a new division cycle in budding yeast occurs earlier in mother cells than in daughter cells. The lysine deacetylase Hos3 has been implicated in the control of G1 length.