Identification of the Polypyrimidine Tract Binding Protein-associated Splicing Factor·p54(nrb) Complex as a Candidate DNA Double-strand Break Rejoining Factor

Abstract

The biological effects of ionizing radiation are attributable, in large part, to induction of DNA double-strand breaks. We report here the identification of a new protein factor that reconstitutes efficient double-strand break rejoining when it is added to a reaction containing the five other polypeptides known to participate in the human nonhomologous end-joining pathway. The factor is a stable heteromeric complex of polypyrimidine tract-binding protein-associated splicing factor (PSF) and a 54-kDa nuclear RNA-binding protein (p54(nrb)). These polypeptides, to which a variety of functions have previously been attributed, share extensive homology, including tandem RNA recognition motif domains. The PSF⅐p54(nrb) complex cooperates with Ku protein to form a functional preligation complex with substrate DNA. Based on structural comparison with related proteins, we propose a model where the four RNA recognition motif domains in the heteromeric PSF⅐p54(nrb) complex cooperate to align separate DNA molecules.

Gene regulation by SINES and inosines: biological consequences of A-to-I editing of Alu element inverted repeats

“…61 Also, this complex might participate in DNA repair as a DNA double-strand break rejoining factor. 72 More recently, p54 nrb /PSF with the single Alu containing RNA where the majority (73%) of messengers distributed only in the cytoplasm. Binding to p54 nrb positively correlated with both promiscuous editing and selective nuclear retention.…”

Arginine methylation and citrullination of splicing factor proline- and glutamine-rich (SFPQ/PSF) regulates its association with mRNA

“…More recently, SFPQ/NONO were shown to be stimulatory factors for U snRNA export (Izumi et al 2014) and DNA topoisomerase I (Straub et al 1998(Straub et al , 2000 together with a role in the nonhomologous end joining response to DNA double strand breaks (Bladen et al 2005). SFPQ also acts as a transcriptional regulator recruiting Sin3a, which in turn recruits histone deacetylase (HDAC) thus repressing transcription (Mathur et al 2001;Sewer et al 2002;Dong et al 2007).…”

The Splicing Factor PSF is Part of a Large Complex That Assembles in the Absence of pre-mRNA and Contains All 5 snRNPs

“…It has been shown to act as a transcriptional regulator in several different cases, such as regulation of growth factor stimulated gene expression, 33,34 as a corepressor acting through Sin3A to recruit histone deacetylases (HDACs) and induce silencing, 35 and as part of a complex that activates the human CYP17 promoter in response to cAMP stimulation. 36,37 PSF has also been implicated in the regulation of topoisomerase I activity, 27,38 as a DNA doublestranded break repair factor, 39 and in nuclear retention of hyper-edited RNAs. 40 Lastly, PSF has been shown to repress the expression of HIV-1 gag/pol and env mRNAs through cis-acting instability elements (INS) that target degradation.…”