PABPN1

Official Full Name

poly(A) binding protein nuclear 1

Organism

Homo sapiens

GeneID

8106

Background

This gene encodes an abundant nuclear protein that binds with high affinity to nascent poly(A) tails. The protein is required for progressive and efficient polymerization of poly(A) tails at the 3' ends of eukaryotic transcripts and controls the size of the poly(A) tail to about 250 nt. At steady-state, this protein is localized in the nucleus whereas a different poly(A) binding protein is localized in the cytoplasm. This gene contains a GCG trinucleotide repeat at the 5' end of the coding region, and expansion of this repeat from the normal 6 copies to 8-13 copies leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. Related pseudogenes have been identified on chromosomes 19 and X. Read-through transcription also exists between this gene and the neighboring upstream BCL2-like 2 (BCL2L2) gene. [provided by RefSeq, Dec 2010]

Synonyms

OPMD; PAB2; PABII; PABP2; PABP-2;

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Detailed Information

Pabpn1 works as a suppressive factor controlling alternative cleavage and polyadenylation (APA)

In the gene regulation process, alternative cleavage and polyadenylation (APA) contributes a lot, however, factors controlling APA remains to be elusive. RNAi screen for APA was used to identified Pabpn1 as a regulator. And the loss of Pabpn1 induced extensive 3’ untranslated region shortening was found in human cells by Genome-wide analysis of APA. Proximal cleavage sites (CSs) usage enhancement was revealed to be the underlying mechanism by messenger RNA transcription, stability analyses, and in vitro cleavage assays. Triplet-repeat expansion in Pabpn1 in mouse model of OPMD (oculopharyngeal muscular dystrophy) and human cells induced proximal CS usage enhancement, which is linked with binding to endogenous Pabpn1 and sequestration in nuclear aggregates.

Gene therapy developed from Pabpn1 for oculopharyngeal muscular dystrophy (OPMD)

As an autosomal dominant, degenerative muscle disease, oculopharyngeal muscular dystrophy (OPMD) is affecting 1/100000 people in Europe that usually presents in the fifth decade of life. The characterizations of OPDA mainly included by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. Mutation in the Pabpn1 gene in OPMD affected individuals is ubiquitously involved in many biological processes. Pabpn1 is responsible for the polyadenylate polymerase and control of poly(A) tail length on RNA transcripts. And it also has involvement in long non-coding RNA and small nucleolar RNA processing, nuclear surveillance for hyperadenylation and decay of RNA. Pabpn1 mutation of alanine-encoding (GCN)n trinucleotide repeat expansion with 11-18 repeats instead of the normal 10 present in normal one. Tendentiousness of misfolded resulting protein (expPABPN1) aggregating into insoluble aggregates in nuclear is considered to be the main histopathological hallmark of the disease. Gene therapy approach by using RNA interference (RNAi) demonstrated in a mouse model of OPMD to inhibit Pabpn1 expression both in wild type and expanded express a sequenced-optimized normal Panpn1 resistant to RNA-induced cleavage. Depletion of endogenous Pabpn1 can abolish nuclear aggregates but with the consequence of muscle degeneration. While Adeno-associated virus (AAV) mediated accompanied with the RNAi therapy can significantly improve the pathology.

Pabpn1 Figure 1. Implication of PABPN1 in post-transcriptional functions within the nucleus including poly(A) tail length control and poly(A) cleavage site selection. (Ayan Banerjee, et al. 2013)

References:

Jenal M, Elkon R, Loayza-Puch F, et al. The poly (A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell, 2012, 149(3): 538-553.
Banerjee A, Apponi L H, Pavlath G K, et al. PABPN 1: molecular function and muscle disease. The FEBS journal, 2013, 280(17): 4230-4250.

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