p53 mediated regulation of LINE1 retrotransposition derived R-loops

Abstract

LINE1/L1 transposons, comprising around 20% of the human genome, typically remain quiescent in healthy somatic cells but become activation in various cancer types. Our recent investigation reveals that p53 acts on L1 promoter to supress these repetitive sequences, potentially constituting a tumor suppressive pathway. In this study, we observe that p53 silences L1mRNA-cDNA hybrids (trans R-loops) formed during retrotransposition. We show that activation of L1 by HDAC inhibitors (HDACi) leads to the accumulation of L1mRNA-cDNA hybrids in p53-/- cells, which were mitigated by treatment with the reverse transcriptase inhibitor. Furthermore, we demonstrate that p53 aids in re-silencing of hyperactivated L1 induced by HDACi by recruiting histone repressive marks, specifically H3K9me3 and H3K27me3 to the L1-5′UTR and inhibiting the deposition of H3K4me3 and H3K9ac marks. This study highlights a novel role of p53 in reinstating the suppression of activated L1 and regulating R-loops derived from retrotransposition, thus maintaining genome stability and modulating the expression of inflammatory genes.