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ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

Author

Listed:
  • Su Hyung Park

    (Institute for Basic Science)

  • Nalae Kang

    (Institute for Basic Science)

  • Eunho Song

    (Seoul National University
    Seoul National University)

  • Minwoo Wie

    (Ulsan National Institute of Science and Technology)

  • Eun A. Lee

    (Institute for Basic Science)

  • Sunyoung Hwang

    (Institute for Basic Science)

  • Deokjae Lee

    (Ulsan National Institute of Science and Technology
    Medytox Inc. 114)

  • Jae Sun Ra

    (Institute for Basic Science)

  • In Bae Park

    (Institute for Basic Science)

  • Jieun Park

    (Institute for Basic Science)

  • Sukhyun Kang

    (Institute for Basic Science)

  • Jun Hong Park

    (Institute for Basic Science)

  • Sungchul Hohng

    (Seoul National University
    Seoul National University
    Seoul National University)

  • Kyoo-young Lee

    (Institute for Basic Science)

  • Kyungjae Myung

    (Institute for Basic Science
    Ulsan National Institute of Science and Technology)

Abstract

Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2ʹ-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress.

Suggested Citation

  • Su Hyung Park & Nalae Kang & Eunho Song & Minwoo Wie & Eun A. Lee & Sunyoung Hwang & Deokjae Lee & Jae Sun Ra & In Bae Park & Jieun Park & Sukhyun Kang & Jun Hong Park & Sungchul Hohng & Kyoo-young Le, 2019. "ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13667-4
    DOI: 10.1038/s41467-019-13667-4
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