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AND-1 fork protection function prevents fork resection and is essential for proliferation

Author

Listed:
  • Takuya Abe

    (IFOM, the FIRC Institute of Molecular Oncology
    Tokyo Metropolitan University)

  • Ryotaro Kawasumi

    (IFOM, the FIRC Institute of Molecular Oncology)

  • Michele Giannattasio

    (IFOM, the FIRC Institute of Molecular Oncology
    Università degli Studi di Milano)

  • Sabrina Dusi

    (IFOM, the FIRC Institute of Molecular Oncology)

  • Yui Yoshimoto

    (Tokyo Metropolitan University)

  • Keiji Miyata

    (Tokyo Metropolitan University)

  • Koyuki Umemura

    (Tokyo Metropolitan University)

  • Kouji Hirota

    (Tokyo Metropolitan University)

  • Dana Branzei

    (IFOM, the FIRC Institute of Molecular Oncology
    Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR))

Abstract

AND-1/Ctf4 bridges the CMG helicase and DNA polymerase alpha, facilitating replication. Using an inducible degron system in avian cells, we find that AND-1 depletion is incompatible with proliferation, owing to cells accumulating in G2 with activated DNA damage checkpoint. Replication without AND-1 causes fork speed slow-down and accumulation of long single-stranded DNA (ssDNA) gaps at the replication fork junction, with these regions being converted to DNA double strand breaks (DSBs) in G2. Strikingly, resected forks and DNA damage accumulation in G2, but not fork slow-down, are reverted by treatment with mirin, an MRE11 nuclease inhibitor. Domain analysis of AND-1 further revealed that the HMG box is important for fast replication but not for proliferation, whereas conversely, the WD40 domain prevents fork resection and subsequent DSB-associated lethality. Thus, our findings uncover a fork protection function of AND-1/Ctf4 manifested via the WD40 domain that is essential for proliferation and averts genome instability.

Suggested Citation

  • Takuya Abe & Ryotaro Kawasumi & Michele Giannattasio & Sabrina Dusi & Yui Yoshimoto & Keiji Miyata & Koyuki Umemura & Kouji Hirota & Dana Branzei, 2018. "AND-1 fork protection function prevents fork resection and is essential for proliferation," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05586-7
    DOI: 10.1038/s41467-018-05586-7
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    Cited by:

    1. Sameer Bikram Shah & Youhang Li & Shibo Li & Qing Hu & Tong Wu & Yanmeng Shi & Tran Nguyen & Isaac Ive & Linda Shi & Hailong Wang & Xiaohua Wu, 2024. "53BP1 deficiency leads to hyperrecombination using break-induced replication (BIR)," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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