Abstract
ABSTRACTDNA endoreplication has been implicated as a cell strategy for cell growth and in tissue injury. Here, we demonstrate that barrier-to-autointegration factor (BAF) represses endoreplication in Drosophila myofibers. We show that BAF localization at the nuclear envelope is eliminated in flies with mutations of the linker of nucleoskeleton and cytoskeleton (LINC) complex in which the LEM-domain protein Otefin is excluded, or after disruption of the nucleus-sarcomere connections. Furthermore, BAF localization at the nuclear envelope requires the activity of the BAF kinase VRK1/Ball, and, consistently, non-phosphorylatable BAF-GFP is excluded from the nuclear envelope. Importantly, removal of BAF from the nuclear envelope correlates with increased DNA content in the myonuclei. E2F1, a key regulator of endoreplication, overlaps BAF localization at the myonuclear envelope, and BAF removal from the nuclear envelope results in increased E2F1 levels in the nucleoplasm and subsequent elevated DNA content. We suggest that LINC-dependent and phosphosensitive attachment of BAF to the nuclear envelope, through its binding to Otefin, tethers E2F1 to the nuclear envelope thus inhibiting its accumulation in the nucleoplasm.
Highlights
Endoreplication emerges as an important strategy of differentiated cells, enabling them to grow in size or rescue tissue integrity following injury, in a wide range of non-dividing cell types (Gan et al, 2019)
barrier-toautointegration factor (BAF) localization at the nuclear envelope depends on a functional linker of nucleoskeleton and cytoskeleton (LINC) complex Previously we showed that the transcription of BAF is significantly reduced in Drosophila larval muscles in the LINC mutants klar and koi, and in addition, knockdown of BAF in these muscles leads to elevated DNA content in the myonuclei (Wang et al, 2018)
BAF labeling at the nuclear envelope was eliminated in the LINC mutant klaroid, lacking a SUN domain protein, and in double homozygous mutants of klar and Msp300 alleles, lacking only the Klarsicht, ANC-1, syne homology (KASH) domain (Fig. 1B-C′′,E,E′,F,F′)
Summary
Endoreplication emerges as an important strategy of differentiated cells, enabling them to grow in size or rescue tissue integrity following injury, in a wide range of non-dividing cell types (Gan et al, 2019). Recent experimental studies have proposed a functional link between mechanical inputs and endoreplication events in various cell types (Cao et al, 2017; Sun et al, 2019). Mechanical signals transmitted across the nuclear membrane have been implicated in the regulation of cell cycle, epigenetic events and gene transcription (Cao et al, 2017; Cho et al, 2017; Kirby and Lammerding, 2018). As part of the mechanism linking cell cycle events with mechanical inputs, the translocation of specific essential factors into the nucleus has been proposed (Aragona et al, 2013; Driscoll et al, 2015; Dupont et al, 2011; Ho et al, 2013; Kassianidou et al, 2019).
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