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      Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication

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          Abstract

          LINE-1 retrotransposons are overexpressed in more than half of human cancers. We identified a colorectal cancer wherein a fast-growing tumor subclone downregulated LINE-1, prompting us to examine how LINE-1 expression affects cell growth. We find that non-transformed cells undergo a TP53-dependent growth arrest and activate interferon signaling in response to LINE-1. TP53 inhibition allows LINE-1(+) cells to grow, and genome wide knockout screens show that these cells require replication-coupled DNA repair pathways, replication stress signaling, and replication fork restart factors. Our findings demonstrate that LINE-1 expression creates specific molecular vulnerabilities and reveal a retrotransposition-replication conflict that may be an important determinant of cancer growth.

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          Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition.

          D. D. Luan, M Korman, J L Jakubczak … (1993)
          R2 is a non-LTR retrotransposable element that inserts at a specific site in the 28S rRNA genes of most insects. We have expressed the open reading frame of the R2 element from Bombyx mori, R2Bm, in E. coli and shown that it encodes both sequence-specific endonuclease and reverse transcriptase activities. The R2 protein makes a specific nick in one of the DNA strands at the insertion site and uses the 3' hydroxyl group exposed by this nick to prime reverse transcription of its RNA transcript. After reverse transcription, cleavage of the second DNA strand occurs. A similar mechanism of insertion may be used by other non-LTR retrotransposable elements as well as short interspersed nucleotide elements.
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            Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress.

            I Ward, J. Chen (2001)
            H2AX, a member of the histone H2A family, is rapidly phosphorylated in response to ionizing radiation. This phosphorylation, at an evolutionary conserved C-terminal phosphatidylinositol 3-OH-kinase-related kinase (PI3KK) motif, is thought to be critical for recognition and repair of DNA double strand breaks. Here we report that inhibition of DNA replication by hydroxyurea or ultraviolet irradiation also induces phosphorylation and foci formation of H2AX. These phospho-H2AX foci colocalize with proliferating cell nuclear antigen (PCNA), BRCA1, and 53BP1 at the arrested replication fork in S phase cells. This response is ATR-dependent but does not require ATM or Hus1. Our findings suggest that, in addition to its role in the recognition and repair of double strand breaks, H2AX also participates in the surveillance of DNA replication.
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              Natural mutagenesis of human genomes by endogenous retrotransposons.

              Rebecca C. Iskow, Michael T. McCabe, Ryan E. Mills … (2010)
              Two abundant classes of mobile elements, namely Alu and L1 elements, continue to generate new retrotransposon insertions in human genomes. Estimates suggest that these elements have generated millions of new germline insertions in individual human genomes worldwide. Unfortunately, current technologies are not capable of detecting most of these young insertions, and the true extent of germline mutagenesis by endogenous human retrotransposons has been difficult to examine. Here, we describe technologies for detecting these young retrotransposon insertions and demonstrate that such insertions indeed are abundant in human populations. We also found that new somatic L1 insertions occur at high frequencies in human lung cancer genomes. Genome-wide analysis suggests that altered DNA methylation may be responsible for the high levels of L1 mobilization observed in these tumors. Our data indicate that transposon-mediated mutagenesis is extensive in human genomes and is likely to have a major impact on human biology and diseases.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101186374
                Journal ID (pubmed-jr-id): 31761
                Journal ID (nlm-ta): Nat Struct Mol Biol
                Journal ID (iso-abbrev): Nat. Struct. Mol. Biol.
                Title: Nature structural & molecular biology
                ISSN (Print): 1545-9993
                ISSN (Electronic): 1545-9985
                Publication date Nihms-submitted: 1 January 2020
                Publication date (Electronic): 10 February 2020
                Publication date (Print): February 2020
                Publication date PMC-release: 10 August 2020
                Volume: 27
                Issue: 2
                Pages: 168-178
                Affiliations
                [1 ]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [2 ]McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [3 ]Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [4 ]Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, Langone School of Medicine, New York University, New York City, New York, USA
                [5 ]Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
                [6 ]Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
                [7 ]Johns Hopkins Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, Maryland, USA
                [8 ]Institute for NanoBiotechnology, Johns Hopkins University, Baltimore, Maryland, USA
                [9 ]Laboratory of Genome Maintenance, The Rockefeller University, New York Vity, New York, USA
                [10 ]Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                [11 ]Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
                Author notes

                Author Contributions

                Conceptualization, D.A. and K.H.B.; Methodology, D.A., A.J.H., A.S., and K.H.B.; Formal Analysis, D.A.; Investigation, D.A., J.P.S., P.W., Z.L., C.L., M.G., J.S.S.; Resources, A.S. and A.J.H.; Writing – Original Draft, D.A. and K.H.B.; Writing – Review & Editing, D.A., M.S.T., L.M.P., R.H.H., J.D.B., D.F., A.S., A.J.H., and K.H.B.; Visualization, D.A. and K.H.B.; Supervision, V.D., R.H.H., P.W., D.F., A.S., A.J.H., and K.H.B.; Funding Acquisition, D.A., J.D.B., and K.H.B.

                Article
                Manuscript ID: NIHMS1547649
                DOI: 10.1038/s41594-020-0372-1
                PMC ID: 7080318
                PubMed ID: 32042151
                SO-VID: b6763d40-a6bd-4de5-80e4-964149bb7b26
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: mobile genetic element,fanconi anemia,wrn,blm,hush,crispr-cas9
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: mobile genetic element, fanconi anemia, wrn, blm, hush, crispr-cas9

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