Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication.,Nature Structural & Molecular Biology

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Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication.
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2020-02-10 , DOI: 10.1038/s41594-020-0372-1
Daniel Ardeljan _{1,

2,

3} , Jared P Steranka ₁ , Chunhong Liu ₁ , Zhi Li ₄ , Martin S Taylor ₅ , Lindsay M Payer ₁ , Mikhail Gorbounov ₁ , Jacob S Sarnecki ₆ , Vikram Deshpande ₅ , Ralph H Hruban ₁ , Jef D Boeke ₄ , David Fenyö ₄ , Pei-Hsun Wu _{7,

8} , Agata Smogorzewska ₉ , Andrew J Holland ₁₀ , Kathleen H Burns _{1,

2,

11}

Affiliation

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York City, NY, USA.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA.
Johns Hopkins Physical Sciences Oncology Center, Johns Hopkins University, Baltimore, MD, USA.
Institute for NanoBiotechnology, Johns Hopkins University, Baltimore, MD, USA.
Laboratory of Genome Maintenance, The Rockefeller University, New York City, NY, USA.
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

中文翻译：

细胞适应性筛选揭示了 LINE-1 逆转录转座和 DNA 复制之间的冲突。

LINE-1 逆转录转座子过度表达是人类癌症的一个标志。我们发现了一种结直肠癌，其中快速生长的肿瘤亚克隆下调了 LINE-1，促使我们研究 LINE-1 表达如何影响细胞生长。我们发现，未转化的细胞会经历 TP53 依赖性生长停滞，并响应 LINE-1 激活干扰素信号传导。 TP53 抑制使 LINE-1+ 细胞能够生长，全基因组敲除筛选表明这些细胞需要复制偶联 DNA 修复途径、复制应激信号传导和复制叉重启因子。我们的研究结果表明，LINE-1 表达会产生特定的分子脆弱性，并揭示逆转录转座复制冲突，这可能是癌症生长的重要决定因素。

更新日期：2020-02-10

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