Abstract
While cellular senescence is a critical mechanism to prevent malignant transformation of potentially mutated cells, persistence of senescent cells can also promote cancer and aging phenotypes. NonO/p54nrb and PSF are multifunctional hnRNPs typically found as a complex exclusively within the nuclei of all mammalian cells. We demonstrate here that either increase or reduction of expression of either factor results in cellular senescence. Coincident with this, we observe expulsion of NonO and PSF-containing nuclear paraspeckles and posttranslational modification at G2/M. That senescence is mediated most robustly by overexpression of a cytoplasmic C-truncated form of NonO further indicated that translocation of NonO and PSF from the nucleus is critical to senescence induction. Modulation of NonO and PSF expression just prior to or coincident with senescence induction disrupts the normally heterodimeric NonO-PSF nuclear complex resulting in a dramatic shift in stoichiometry to heterotetramers and monomer with highest accumulation within the cytoplasm. This is accompanied by prototypic cell cycle checkpoint activation and chromatin condensation. These observations identify yet another role for these multifunctional factors and provide a hitherto unprecedented mechanism for cellular senescence and nuclear-cytoplasmic trafficking.
Highlights
Cellular senescence was originally defined as the point in which normal diploid cells cease to divide--generally after ~50 cell divisions in vitro [1]
Following stable transfection of NonO into the 293 Tet-on cell line, clones were obtained but only rarely. This suggested that leaky, uninduced NonO expression above the modest endogenous levels expressed in 293 cells may be toxic
While SA-β-gal a generally accepted criteria for senescence, another reliable marker for true replicative senescence is the presence of senescence-associated heterochromatin foci (SAHF) [40]
Summary
Cellular senescence was originally defined as the point in which normal diploid cells cease to divide--generally after ~50 cell divisions in vitro [1]. This phenomenon, known as "replicative senescence”, can be provoked in response to DNA damage most prominently by telomere shortening [reviewed in 2]. An ensuing DNA damage response (DDR) is associated with the appearance of γ-H2AX and HP1γ positive foci and with DDR protein expression [4]. Communication between DDR-associated factors and cell cycle machinery amplifies the DDR signal into the senescence pathway [5]. Induction of “premature cellular senescence” occurs prior to the stage at which detectable telomere loss or dysfunction is observed [1,6]
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