Dynamics of replication origin over-activation

• Published in: Nature communications Vol. 12; no. 1; pp. 3448 - 15
• Main Authors: Fu, Haiqing, Redon, Christophe E., Thakur, Bhushan L., Utani, Koichi, Sebastian, Robin, Jang, Sang-Min, Gross, Jacob M., Mosavarpour, Sara, Marks, Anna B., Zhuang, Sophie Z., Lazar, Sarah B., Rao, Mishal, Mencer, Shira T., Baris, Adrian M., Pongor, Lorinc S., Aladjem, Mirit I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 14/1; 14/19; 14/63; 38/43; 45/15; 45/22; 45/23; 631/337/151/2352; 631/337/151/2356; 692/4028/67/1059/99; Cancer; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chromatin; Cyclopentanes - pharmacology; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Replication - drug effects; DNA Replication - genetics; Genome, Human; Genomes; Humanities and Social Sciences; Humans; Mitosis - drug effects; Models, Biological; multidisciplinary; Origins; Pyrimidines - pharmacology; Replication; Replication initiation; Replication Origin - genetics; Replication origins; Science; Science (multidisciplinary); Skewed distributions; Synthesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23835-0

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. DNA replication processes are often dysregulated in cancer. Here the authors analyse DNA synthesis patterns in cancer cells undergoing partial genome re-replication to reveal that re-replication exhibits aberrant replication fork dynamics and a skewed distribution of replication initiation that over-duplicates early-replicating genomic regions.