Nuclear pore complexes in the organization of silent telomeric chromatin

The functional regulation of chromatin is closely related to its spatial organization within the nucleus. In yeast, perinuclear chromatin domains constitute areas of transcriptional repression1,2,3. These ‘silent’ domains are defined by the presence of perinuclear telomere clusters4. The only protein found to be involved in the peripheral localization of telomeres is Yku70/Yku80 (ref. 5). This conserved heterodimer6 can bind telomeres7 and functions in both repair of DNA double-strand breaks8,9,10,11 and telomere maintenance7,12,13,14,15. These findings, however, do not address the underlying structural basis of perinuclear silent domains. Here we show that nuclear-pore-complex extensions formed by the conserved TPR16,17 homologues Mlp1 and Mlp218,19 are responsible for the structural and functional organization of perinuclear chromatin. Loss of MLP2 results in a severe deficiency in the repair of double-strand breaks. Furthermore, double deletion of MLP1 and MLP2 disrupts the clustering of perinuclear telomeres and releases telomeric gene repression. These effects are probably mediated through the interaction with Yku70. Mlp2 physically tethers Yku70 to the nuclear periphery, thus forming a link between chromatin and the nuclear envelope. We show, moreover, that this structural link is docked to nuclear-pore complexes through a cleavable nucleoporin, Nup14520. We propose that, through these interactions, nuclear-pore complexes organize a nuclear subdomain that is intimately involved in the regulation of chromatin metabolism.