Dynamics of replication origin over-activation

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 Rao, Shira T. Mencer, Adrian M. Baris, Lorinc S. Pongor and Mirit I. Aladjem ()
Additional contact information
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
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
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23835-0

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