SERBP1 interactome defines its novel regulatory roles in the cytoplasm and nucleus in conjunction with PARP1-, G-quadruplex- and PAR-binders
RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics allow liquid-liquid phase separation (LLPS) and formation of membraneless organelles or molecular condensates such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system, regulating brain function, neurogenesis and synapse plasticity. Their dysfunction is associated with neurodegenerative diseases and brain tumor development.  SERBP1 is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. We have previously defined SERBP1 as an oncogenic factor in glioblastoma. Here, we investigated the SERBP1 interactome using a proteomics approach. We defined novel roles for SERBP1 in splicing, cell division, DNA repair and ribosomal biogenesis based on the protein's interactome and functional analyses. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, SERBP1 and most of its associated proteins get PARylated and/or bind to PAR, indicating that SERBP1 is present in regulatory complexes that are built on PAR binding. Finally, we determined that SERBP1 is potentially implicated in Alzheimer's where it is highly expressed and present in pathological stress granules and Tau aggregates. In conclusion, our study established SERBP1 as a multi-functional protein that participates in distinct regulatory complexes assembled via G4- and PAR-binding.