Altered stoichiometry and nuclear delocalization of NonO and PSF promote cellular senescence

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.

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

“…In response to peroxide exposure, multiple factors linking oxidative stress to DNA damage management and senescence were found to physically associate with RXFP3 receptorsomes including PRDX6 [65, 66], PCNA [67, 68], FUS [69], RBMX [70], PARP1 [71], PRDX1 [72–74], SOD1 [75, 76], LDHB [77] and YBX1 [78]. In response to a DNA damaging perturbagen, multiple factors linking cellular stress to DNA damage management, senescence and organismal longevity were also found to be physically associated with RXFP3 receptorsomes, including PHB2 [79–82], TRAP1 [83, 84], AIMP1 [85, 86], KPNA2 [87, 88], TUFM [89], EMD [90, 91], MAT2A [92, 93], NONO [94-100], IGFBP2 [101–103], SNRPA1 [104], HNRNPF [105], FAM98A [106] and ELAVL1 [107–110]. It is likely that during pathological aging, the generation of oxygen radicals, e.g.…”

The cell adhesion molecule L1 interacts with nuclear proteins via its intracellular domain

“…NonO, SFPQ, and PSP1 contain a DBHS domain composed of two RNA recognition motifs and a DNA binding domain 74,75 . They act as RNA‐ and DNA‐binding proteins in biogenesis, processing and transport of RNA, transcription, telomere stability, and DNA repair, and are located in paraspeckles 39,74‐95 . Moreover, NonO is associated with intellectual disability 95,96 .…”

Liquid–liquid phase separation in tumor biology

“…Regulator of RNA:DNA hybrid related telomere instability. 335 – 337 Paraspeckles influence the tumor stability to develop drugs resistance. 338 SFPQ Paraspeckle Nucleus and cytoplasm 1.…”