p53 mediated regulation of LINE1 retrotransposon derived R-loops

Long Interspersed Nuclear Element 1 (LINE1/L1) retrotransposons, comprising around 17% of the human genome, typically remain quiescent in healthy somatic cells but become activated in various cancer types. Our recent investigation reveals that p53 silences L1 transposons in human somatic cells, potentially constituting a tumor suppressive pathway. In this study, we demonstrate that p53 silences both L1mRNA-gDNA (cis L1 R-loops) and L1mRNA-cDNA hybrids (trans L1 R-loops) formed during retrotransposition. The activation of L1 transposons by HDAC inhibitors (HDACi) led to accumulation of these cis and trans L1 R-loops in p53-/- cells, which were mitigated by treatment with a reverse transcriptase inhibitor. Furthermore, p53 established re-silencing of hyperactivated L1 transposons induced by HDACi. The p53-mediated restoration of silencing was accompanied by recruiting histone repressive marks specifically H3K9me3 and H3K27me3 and inhibiting the deposition of H3K4me3 and H3K9ac marks at the L1 promoter. This study elucidates a novel role of p53 in regulating the formation of RNA-DNA hybrids, a pivotal intermediate component of retrotransposition, and initiating the suppression of hyperactivated L1 elements. These findings underscore the significance of p53 in preserving genome stability through the regulation of L1-derived R-loops. In BriefThe role of L1 transposon derived L1mRNA-cDNA hybrids; an intermediate product formed during retrotransposition, in DNA damage and inflammation is not clear. Paul et al. reveals that p53 prevents L1cDNA derived RNA-DNA hybrids to control DNA damage and activation of inflammatory genes. The findings also elucidate the role of p53 in initiating the repression of hyperactivated transposons by facilitating the recruitment of epigenetic repressive marks and preventing the deposition of activating marks at L1-5UTR. HighlightsO_LIp53 loss facilitates accumulation of both cis (L1mRNA-gDNA) and trans (L1mRNA-cDNA) forms of L1 R-loops. C_LIO_LIThe youngest, actively retrotransposing full-length L1s contribute to the formation of trans (L1mRNA-cDNA) R-loops. C_LIO_LIp53 aids immediate L1 re-silencing by restoring deposition of epigenetic repressive and inhibition of activating marks. C_LIO_LIReverse transcriptase inhibitor prevents L1 mediated DNA damage. C_LI Subject Categories: L1/LINE1, p53, Retrotransposons, RNA-DNA hybrids, Cis R loops, Trans R-loop, L1/LINE1 Graphical O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/589154v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1e37111org.highwire.dtl.DTLVardef@11430c8org.highwire.dtl.DTLVardef@8e9c0corg.highwire.dtl.DTLVardef@a6e98d_HPS_FORMAT_FIGEXP M_FIG C_FIG