The PRR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting

A large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via “tethering proteins” that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We identified previously a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify a centrally located, evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We also show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation of the LBD. We also show that the evolutionary conserved PRR14 C-terminal Tantalus domain encodes a PP2A phosphatase recognition site that regulates PRR14 nuclear lamina association. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two modular domains. Furthermore, the identification of a modular LBD may provide an engineering strategy for delivery of cargo to the nuclear lamina.