Fig. 1(A) 3′-End processing complexes and cis-acting elements of the 3′-last exon for polyadenylation. RNA polymerase II C-terminal domain (CTD) is associated with many 3′-end processing proteins. The combination of upstream sequence elements (USE), downstream sequence element (DSE), and polyadenylation signal (PAS) is used to determine the cleavage site of a transcript during transcription termination. (B) Alternative polyadenylation (APA) and its effect on protein production. In 3′-untranslated region (UTR) APA, the usage of proximal PAS can be increased or decreased by cleavage stimulation factor (CSFT) 2 or cleavage and polyadenylation specificity factor (CPSF) 5/6 respectively. The length of 3′-UTR could affect the interaction with microRNA (miRNAs) or RNA-binding proteins (RBPs) and modulate protein synthesis. APA in intron regions could affect the coding capacity of protein and thus produce truncated protein. CF, cleavage factor; PCF11, PCF11 cleavage and polyadenylation factor subunit; CLP1, cleavage and polyadenylation factor I subunit 1; WDR33, WD repeat domain 33; FIP1L1, factor interacting with PAPOLA and CPSF1; ATG, initiation codon; TAA, termination codon; TSS, transcription start site.
Table 1Summary of Alternative Polyadenylation Related Diseases
Classification |
Disease and/or condition |
Target gene |
Mechanism |
Reference |
Endocrine |
Steroidogenesis |
STAR |
Br-cAMP stimulates distal PAS usage |
[9] |
Diabetic nephropathy |
HGRG-14 |
High-glucose level leads to distal PAS usage |
[12] |
Type 2 diabetes |
TCF7L2 |
Increased different isoforms by usage of intronic PAS |
[17] |
Hematological |
β-Thalassemia |
HBB |
Elongated 3'UTR region and transcription termination defects by mutations on polyadenylation site |
[18,19] |
α-Thalassemia |
HBA1 |
|
[20,21] |
Tumorigenic |
Proliferative conditions |
RBX1 |
Hyper-activated mTOR leads to usage of proximal PAS |
[24] |
Colorectal cancer |
DMKN, PDXK, and PPIE |
3'UTR shortening has occurred during tumorigenesis |
[25] |
Glioblastoma |
CCND1 |
Knockdown of CPSF5 induces 3'UTR shortening |
[23] |
Infection and immunological |
B-cell differentiation |
IGHM |
CSTF2 leads to proximal PAS usage |
[52] |
T-cell activation |
NF-ATC1 |
Upregulation of CSTF2 stimulates 3'UTR shortening during T-cells activation |
[30] |
Systemic lupus erythematosus |
GIMAP5 |
Disruption of proximal PAS by mutation |
[34] |
IPEX syndrome |
FOXP3 |
Mutations on first PAS |
[35] |
Neurological |
Parkinson disease |
SNCA |
PD risk factor induces shorter isoform |
[45] |
Oculopharyngeal muscular dystrophy |
CCND1 |
PABPN1 suppresses usage of proximal weaker PAS |
[49] |
Huntington's disease |
HTT |
Depletion of CNOT6 induces isoform shift |
[50] |