De, A. K. | Search bioRxiv

bioRxiv2024

p53 restores the silencing of activated L1 Transposons

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

cancer biology↗

bioRxiv2022

Comparative Radiopathology of Male Reproductive Organs in Sprague Dawley Rats Administered with Curcuma longa and Ocimum sanctum Against Acute Gamma Irradiation

ObjectiveThe study was designed to evaluate the deleterious e{square}ects of acute lethal gamma irradiation on male reproductive organs of Sprague Dawley rats and the radioprotective potential by Curcuma longa and Ocimum sanctum in experimental set up. Methods25 Male Spraque Dawley rats were taken and randomized into 5 groups (T1, T2, T3, T4, T5). Each group containing 5 animals. The groups were named as Group T1 (Negative Control), Group T2 (irradiation positive control), Group T3 (irradiation and Curcuma longa), Group T4 (irradiation and Ocimum sanctum), Group T5 (irradiation, Curcuma longa and Ocimum sanctum). The rats in groups T1 and T2 were given a daily dosage of normal saline for 14 days. Group T3 and T4 rats received aqueous extracts of Curcuma longa (40 mg/kg) and Ocimum sanctum (40 mg/kg), respectively, whereas group T5 rats received a combination of aqueous extracts of Curcuma longa (40 mg/kg) and Ocimum sanctum (40 mg/kg) for 14 days. prior to gamma irradiation. Animals of group T2, T3, T4, T5 were irradiated with 10 Gy of {gamma} - radiation on 15th day. ResultsExposure of animals to 10 Gy gamma radiation resulted in significant decrease in body weight and testicular weight. Histopathological observations revealed testicular degenerative changes in the seminiferous tubules with primary spermatocytes being most affected and epididymis showed decreased spermatids density with cell debris in the lumen. Pretreatment with Curcuma longa at 40mg/kg for 14 days alleviated the radiation induced pathological changes in testis and epididymis. Curcuma longa demonstrated much better protective effect in combination with Ocimum sanctum in alleviating the radio pathological changes showing the possibility of synergistic effect. However, administration of Ocimum sanctum alone at 40mg/kg for 14 days did not reveal any significant radioprotective property after histomorphological evaluation. ConclusionGamma irradiation of 10 Gy induces severe radio pathological damage to organs of male reproductive system of Spraque Dawley rats. Pre-treatment with Curcuma longa prior to radiotherapy may be effective in preventing radiation-induced damage in the male reproductive organs. Better radioprotection can be achieved with the combination of Curcuma longa and Ocimum sanctum than using alone.

pathology↗