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Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human  transformer 2β  ( TRA2B ) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns.  TRA2B  exon 2 has premature stop codons, whereas an exon 2-containing splice variant ( TRA2β4 ) was expressed preferentially in the nuclei of human colon cancer cells.  TRA2β4  knockdown p53-independently stimulated  CDKN1A  transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that  TRA2β4  interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased  CDKN1A  transcription. Overexpression of  TRA2β4  significantly decreased  CDKN1A  mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together,  TRA2β4  may sequester Sp1 from occupying promoters of target genes including  CDKN1A , promoting cell growth by interrupting the senescence-related gene expression program. This novel function of  TRA2β4  may uncover an oncogenic function of transcribed UCRs.

Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells