1. Chromosomes and Gene Expression
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Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery

  1. Peter Tonzi
  2. Yandong Yin
  3. Chelsea Wei Ting Lee
  4. Eli Rothenberg
  5. Tony T Huang  Is a corresponding author
  1. New York University School of Medicine, United States
Research Article
  • Cited 6
  • Views 1,492
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Cite this article as: eLife 2018;7:e41426 doi: 10.7554/eLife.41426

Abstract

DNA replication stress is often defined by the slowing or stalling of replication fork progression leading to local or global DNA synthesis inhibition. Failure to resolve replication stress in a timely manner contribute towards cell cycle defects, genome instability and human disease; however, the mechanism for fork recovery remains poorly defined. Here we show that the translesion DNA polymerase (Pol) kappa, a DinB orthologue, has a unique role in both protecting and restarting stalled replication forks under conditions of nucleotide deprivation. Importantly, Pol kappa-mediated DNA synthesis during hydroxyurea (HU)-dependent fork restart is regulated by both the Fanconi Anemia (FA) pathway and PCNA polyubiquitination. Loss of Pol kappa prevents timely rescue of stalled replication forks, leading to replication-associated genomic instability, and a p53-dependent cell cycle defect. Taken together, our results identify a previously unanticipated role for Pol kappa in promoting DNA synthesis and replication stress recovery at sites of stalled forks.

Article and author information

Author details

  1. Peter Tonzi

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yandong Yin

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2499-871X
  3. Chelsea Wei Ting Lee

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Eli Rothenberg

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tony T Huang

    Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States
    For correspondence
    tony.huang@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9291-5002

Funding

National Institutes of Health (ES025166)

  • Peter Tonzi

National Institutes of Health (GM108119)

  • Yandong Yin
  • Chelsea Wei Ting Lee

American Cancer Society (RSG-16-241-01-DMC)

  • Yandong Yin
  • Chelsea Wei Ting Lee

V Foundation for Cancer Research

  • Eli Rothenberg
  • Tony T Huang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andre Nussenzweig

Publication history

  1. Received: August 24, 2018
  2. Accepted: November 12, 2018
  3. Accepted Manuscript published: November 13, 2018 (version 1)
  4. Version of Record published: November 23, 2018 (version 2)

Copyright

© 2018, Tonzi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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