Polyadenylate-binding protein nuclear 1 (PABPN1) (PABPN1)

Polyadenylate-binding protein nuclear 1 (PABPN1) is an essential RNA-binding protein that plays a central role in the nuclear phase of messenger RNA (mRNA) processing (UniProt: P46338). It binds to the growing poly(A) tail of pre-mRNAs, stimulating the activity of poly(A) polymerase and acting as a molecular ruler to define the final tail length of approximately 250 nucleotides, which is vital for mRNA stability and nuclear export (NCBI Gene: 8106). PABPN1 is also involved in the regulation of alternative polyadenylation, thereby influencing the diversity of the cellular transcriptome. The protein is the primary driver of Oculopharyngeal Muscular Dystrophy (OPMD), a late-onset disease caused by a GCG trinucleotide repeat expansion in the first exon of the PABPN1 gene, leading to an expanded polyalanine tract (OMIM: 602279). This mutation causes the protein to form toxic, insoluble intranuclear inclusions in skeletal muscle, resulting in progressive muscle weakness. Therapeutic development is currently focused on "silence and replace" gene therapies, such as BB-301, which utilize RNA interference to deplete the mutant protein while restoring functional wild-type PABPN1 (PubMed: 29656863). Additionally, small molecules like trehalose and guanabenz are being investigated for their potential to reduce protein aggregation and mitigate the cellular stress caused by the mutant protein (PubMed: 25107473).

Other names

PABP2PAB2PABP-2Poly(A) binding protein 2Poly(A) binding protein nuclear 1

RNA interference-mediated knockdown of mutant PABPN1 combined with codon-optimized wild-type PABPN1 replacement (silence and replace); small molecule inhibition of protein aggregation and modulation of the protein folding environment.