NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer

Ludlow et al., Nature Communications, 2018, asked what decides whether the telomerase catalytic subunit hTERT is spliced into its active full length form or into an inactive isoform that skips two exons, and answered it with the splicing factor NOVA1. A screen of 528 small interfering RNA pools against an hTERT minigene, crossed with expression correlations across lung cancer lines, narrowed the field to four splicing factors, and NOVA1 was chosen from those four as the only one whose expression is tissue restricted. Knocking it down shifted the transcript to the inactive isoform, cut telomerase activity and shortened telomeres, and crosslinking placed NOVA1 on a 258 base pair element inside intron 8 called direct repeat 8.

The oligonucleotide experiment sits at the end of that argument. An antisense oligonucleotide covering 19 nucleotides at one end of that element, including one of its binding motifs, was applied at 50 nM for 48 hours to two lung cancer lines chosen as a matched pair: one that expresses NOVA1 and one that does not. In the line with the factor, splicing shifted toward the exon skipped isoform. In the line without it, nothing moved. That contrast is what showed the element is a splicing enhancer only when its factor is present, and it agrees with what deleting the element from the genome did.

Two cautions belong with any use of this paper. AUM is not named anywhere in it. The attribution rests entirely on the chemistry named once in a supplementary figure legend, which is AUM's own. And the paper disagrees with itself on the statistics for that panel: the main text calls the shift significant and the supplementary legend reports the test as not significant across three biological replicates. The paper also never describes how the oligo was delivered.