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Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication.
Ardeljan, Daniel; Steranka, Jared P; Liu, Chunhong; Li, Zhi; Taylor, Martin S; Payer, Lindsay M; Gorbounov, Mikhail; Sarnecki, Jacob S; Deshpande, Vikram; Hruban, Ralph H; Boeke, Jef D; Fenyö, David; Wu, Pei-Hsun; Smogorzewska, Agata; Holland, Andrew J; Burns, Kathleen H.
Afiliação
  • Ardeljan D; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
  • Steranka JP; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
  • Liu C; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ardeljan@jhmi.edu.
  • Li Z; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Taylor MS; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Payer LM; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA.
  • Gorbounov M; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • Sarnecki JS; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Deshpande V; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Hruban RH; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Boeke JD; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
  • Fenyö D; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Wu PH; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA.
  • Smogorzewska A; Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA.
  • Holland AJ; Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, MD, USA.
  • Burns KH; Institute for NanoBiotechnology, Johns Hopkins University, Baltimore, MD, USA.
Nat Struct Mol Biol ; 27(2): 168-178, 2020 02.
Article em En | MEDLINE | ID: mdl-32042151
ABSTRACT
LINE-1 retrotransposon overexpression is a hallmark 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 nontransformed 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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA / Elementos Nucleotídeos Longos e Dispersos / Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: DNA / Elementos Nucleotídeos Longos e Dispersos / Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article