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Impediment of Replication Forks by Long Non-coding RNA Provokes Chromosomal Rearrangements by Error-Prone Restart

  1. Author:
    Watanabe, Takaaki
    Marotta, Michael
    Suzuki, Ryusuke
    Diede, Scott J
    Tapscott, Stephen J
    Niida, Atsushi
    Chen, Jack
    Mouakkad, Lila
    Kondratova, Anna
    Giuliano, Armando E
    Orsulic, Sandra
    Tanaka, Hisashi

  2. Author Address

    Cedars-Sinai Medical Center, West Hollywood, CA 90048, USA; Department of Molecular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA., Cedars-Sinai Medical Center, West Hollywood, CA 90048, USA., Division of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA., Division of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan., Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc., National Cancer Institute at Frederick, Frederick, MD 21701, USA., Cedars-Sinai Medical Center, West Hollywood, CA 90048, USA; Department of Molecular Genetics, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA. Electronic address: hisashi.tanaka@cshs.org.,
    1. Year: 2017
    2. Date: Nov 21
  2. Journal: Cell reports
    1. 21
    2. 8
    3. Pages: 2223-2235
  4. Type of Article: Article
  5. ISSN: 2211-1247
  1. Abstract:

    Naturally stalled replication forks are considered to cause structurally abnormal chromosomes in tumor cells. However, underlying mechanisms remain speculative, as capturing naturally stalled forks has been a challenge. Here, we captured naturally stalled forks in tumor cells and delineated molecular processes underlying the structural evolution of circular mini-chromosomes (double-minute chromosomes; DMs). Replication forks stalled on the DM by the co-directional collision with the transcription machinery for long non-coding RNA. RPA, BRCA2, and DNA polymerase eta (Pol?) were recruited to the stalled forks. The recruitment of Pol? was critical for replication to continue, as Pol? knockdown resulted in DM loss. Rescued stalled forks were error-prone and switched replication templates repeatedly to create complex fusions of multiple short genomic segments. In mice, such complex fusions circularized the genomic region surrounding MYC to create a DM during tumorigenesis. Our results define a molecular path that guides stalled replication forks to complex chromosomal rearrangements. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.celrep.2017.10.103
  3. PMID: 29166612
  4. View record in Web of Science®
  5. WOS: 000416216700018
  6. PII : S2211-1247(17)31583-8

Library Notes

  1. Fiscal Year: FY2017-2018
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