Mechanosensitive, phospho-dependent recruitment of BAF to the nuclear membrane inhibits nuclear entrance of E2F1 and Yap/Yorkie

Mechanotransduction has been implicated as an important factor in regulating cell cycle progression; however, the underlying mechanism has not been fully elucidated. Here, we describe a novel mechano-sensitive component, namely barrier to autointegration factor (BAF), which regulates DNA replication (endoreplication) in Drosophila melanogaster muscle fibers. BAF, a small protein, regulates dsDNA assembly post-mitotically, and sealing of nuclear membrane ruptures. We show that in fully differentiated muscle fibers BAF negatively regulates DNA endoreplication by inhibiting of the nuclear entrance of E2F1 and Yap/Yorkie, two key components in cell cycle control. Furthermore, we show that BAF localization at the nuclear membrane is mechanosensitive, as it was downregulated in LINC mutant larval muscles, or following nuclear deformation caused by disruption of nucleus-sarcomere connections. We then show that BAF forms a protein complex with E2F1, which is sensitive to BAF phosphorylation. Knockdown of BAF kinase VRK1/Ball disrupted localization of BAF at the nuclear membrane and resulted in increased E2F1 nuclear levels. Taken together, our results reveal a novel mechanosensitive pathway controlling BAF phosphorylation and localization at the nuclear membrane, which in turn, represses nuclear accumulation of positive cell cycle regulators.