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Dynamics of replication origin over-activation

Author

Listed:
  • Haiqing Fu

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Christophe E. Redon

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Bhushan L. Thakur

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Koichi Utani

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
    Kanazawa Medical University)

  • Robin Sebastian

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Sang-Min Jang

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
    Chungbuk National University)

  • Jacob M. Gross

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Sara Mosavarpour

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Anna B. Marks

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Sophie Z. Zhuang

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Sarah B. Lazar

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Mishal Rao

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Shira T. Mencer

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Adrian M. Baris

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
    Oregon Health and Science University)

  • Lorinc S. Pongor

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

  • Mirit I. Aladjem

    (Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute)

Abstract

Safeguards against excess DNA replication are often dysregulated in cancer, and driving cancer cells towards over-replication is a promising therapeutic strategy. We determined DNA synthesis patterns in cancer cells undergoing partial genome re-replication due to perturbed regulatory interactions (re-replicating cells). These cells exhibited slow replication, increased frequency of replication initiation events, and a skewed initiation pattern that preferentially reactivated early-replicating origins. Unlike in cells exposed to replication stress, which activated a novel group of hitherto unutilized (dormant) replication origins, the preferred re-replicating origins arose from the same pool of potential origins as those activated during normal growth. Mechanistically, the skewed initiation pattern reflected a disproportionate distribution of pre-replication complexes on distinct regions of licensed chromatin prior to replication. This distinct pattern suggests that circumventing the strong inhibitory interactions that normally prevent excess DNA synthesis can occur via at least two pathways, each activating a distinct set of replication origins.

Suggested Citation

  • Haiqing Fu & Christophe E. Redon & Bhushan L. Thakur & Koichi Utani & Robin Sebastian & Sang-Min Jang & Jacob M. Gross & Sara Mosavarpour & Anna B. Marks & Sophie Z. Zhuang & Sarah B. Lazar & Mishal R, 2021. "Dynamics of replication origin over-activation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23835-0
    DOI: 10.1038/s41467-021-23835-0
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    Cited by:

    1. Liton Kumar Saha & Sourav Saha & Xi Yang & Shar-yin Naomi Huang & Yilun Sun & Ukhyun Jo & Yves Pommier, 2023. "Replication-associated formation and repair of human topoisomerase IIIα cleavage complexes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Karl-Uwe Reusswig & Julia Bittmann & Martina Peritore & Mathilde Courtes & Benjamin Pardo & Michael Wierer & Matthias Mann & Boris Pfander, 2022. "Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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