@article{118f429d54de41bbaeeed9a741e26415,
title = "P53 directly represses human LINE1 transposons",
abstract = "p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5?UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.",
keywords = "LINE1, P53, Transrepression, Tumor suppressors",
author = "Bhavana Tiwari and Jones, {Amanda E.} and Caillet, {Candace J.} and Simanti Das and Royer, {Stephanie K.} and Abrams, {John M.}",
note = "Funding Information: We thank N.L. and T.S. (University of Texas Southwestern Flow Cytometry) for their assistance in FACS. We thank the McDer-mott Center Next-Generation Core Facility at University of Texas Southwestern. We thank J.R.P. from the Jerry Shay laboratory at University of Texas Southwestern for intellectual input in p53 KO generation. This work was supported by grants to B.T. and S.D. (Cancer Prevention and Research Institute of Texas [CPRIT] training grant RP160157), A.E.J. (American Cancer Society 128847-PF-15-160-01-DDC), and J.M.A. (National Institutes of Health [NIH] R01GM115682, NIH R01CA222579, and CPRIT RP170086). We acknowledge the assistance of the University of Texas Southwestern Live-Cell Imaging Facility, a shared resource of the Harold C. Simmons Cancer Center, supported in part by National Cancer Institute Cancer Center Support Grant P30 CA142543. We acknowledge the Texas Advanced Computing Center at the University of Texas at Austin (TACC) for providing HPC resources used in the analysis of next-generation sequencing data sets. Publisher Copyright: {\textcopyright} 2020 Cold Spring Harbor Laboratory Press. All rights reserved.",
year = "2020",
month = nov,
day = "1",
doi = "10.1101/gad.343186.120",
language = "English (US)",
volume = "34",
pages = "1439--1451",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "21-22",
}