A shared RNA structural element mediates hnRNP K binding by two divergent lncRNAs in the DNA damage response

LncRNAs are typically poorly conserved at the sequence level, which complicates the use of sequence-based approaches to identify conserved functions. The stress-associated lincRNA-p21 is a paradigm for a sequence-divergent lncRNA. In mice, the interaction between lincRNA-p21 and the hnRNP K protein activates the Cdkn1a gene in cis, encoding the cell-cycle regulator p21, a key effector of the cellular stress response to DNA damage. However, the molecular details of this interaction, and its conservation in other species, remained unknown. To address this, we applied an integrated structural and functional approach, combining in silico, in vitro, ex cellulo, and in cellulo assays. We identified a structural element in mouse and human lincRNA-p21 containing a tetranucleotide motif conserved across more than 100 mammals. This element directly mediates weak binding to the hnRNP K protein in both species, which may enable rapid and reversible modulation of Cdkn1a and timely resolution of the DNA damage response. Conserved hnRNP K binding in humans suggests that the mechanism of Cdkn1a activation may also occur in this species. Our findings establish a shared RNA-protein contact between two syntenic but sequence-divergent transcripts, offering a general strategy for identifying functional RNA elements in other lncRNAs with limited sequence conservation.