br PTEN br Orientation of polyadenylation sites br
Orientation of polyadenylation sites
Fig. 1. APASdb data showing alternative polyadenylation/cleavage sites (CS) and polyadenylation signals (PAS) mapped to the transcript derived from PTEN gene, containing the 5′ and 3′ flanking region of 1 kb. This database identified 61 differentially used alternative CS in the PTEN mRNA processing among 22 normal human tissues (Mean reads: 75, searching dataset: hg19 human-all22-tissues). Position at chromosome 10 (mentioned after “pA” code), PAS sequences and usage quantification (%) are indicated for each CS. As shown in the original APASdb output, the first eleven PTEN polyadenylation sites have their usage quantification depicted by colorful bar charts, while the other sites appear in gray. Of note, two CS located in coding regions (chr10:89726131 and chr10:89726870) had higher usage quantification and were highlighted by rectangles with dashed lines. I.A. Vieira, et al.
Putative polyadenylation signals for cancer predisposition genes without identification of this sequence in NCBI database.
Gene Chr number RefSeq Transcript start Transcript end PAS sequencea PAS start PAS end
Chr Number, chromosome number; PAS, polyadenylation signal.
a A computational method was used to screen 3′-most canonical AAUAAA hexamers and its human functional variants in the full sequence of corresponding transcripts (RefSeq sequences).
MSH6, RAD51, and XPA. Although less oncogenes were included, a larger number of miRNA Galactose 1-phosphate were strongly associated with these genes: mir-128, mir-1471, mir-483, mir-3170 and mir-218. An addi-tional result, important to validate our analysis, refers to mir-34a-5p, a miRNA already known to have tumor suppressor function (Raver-Shapira et al., 2007; Navarro and Lieberman, 2015). This miRNA family was significantly overrepresented as regulator of oncogenes (P = 0.005), and in our analyses we observed validated and predicted interactions with 8 of 17 oncogenes studied (Fig. 2A).
Recent advances have shown that eukaryotic cleavage and poly-adenylation mechanisms are regulated through a network of cis-acting RNA sequence elements (herein termed CPE) located at the pre-mRNA 3′UTR and trans-acting proteins, contributing to the qualitative/quan-titative adjustment of gene expression. The CPE arrangement de-termines the efficiency of a given polyadenylation site (Millevoi and
Vagner, 2010; Hollerer et al., 2014). The most prominent CPE is the PAS, a hexameric sequence motif located 10–30 nt upstream of the CS that was first described by Proudfoot and Brownlee (1976) (Proudfoot and Brownlee, 1976). The PAS serves as a binding site for CPSF, an endonuclease responsible for pre-mRNA cleavage (Ryan et al., 2004). Previous studies indicated that in around 55% of human mRNAs, the PAS hexamer is the AAUAAA consensus sequence (Tian et al., 2005; Beaudoing et al., 2000), recognized as one of the most highly conserved sequence elements known (Proudfoot and Brownlee, 1976; Proudfoot, 2011; Proudfoot, 1991; Wickens and Stephenson, 1984). Most of the remaining mRNAs (~45%) that do not have an exact match to the consensus differ by only a single substitution. An A → U conversion at the second position is the most common PAS variant (AUUAAA) (Tian et al., 2005; MacDonald and Redondo, 2002). Recently, apart from the 12 hexamer variants previously identified (mentioned in the Table 2) (Tian et al., 2005; Beaudoing et al., 2000), six novel motifs conserved between human and mouse were suggested as potential PAS sequences (Gruber et al., 2016).
Frequency of dinucleotide sequences identified as cleavage sites in cancer predisposition genes analyzed in the current study.