Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template

Kai J. Neelsen, Isabella M Y Zanini, Sofija Mijic, Raquel Herrador, Ralph Zellweger, Arnab Ray Chaudhuri, Kevin Creavin, J. Julian Blow, Massimo Lopes (Lead / Corresponding author)

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    47 Citations (Scopus)

    Abstract

    Deregulated origin licensing and rereplication promote genome instability and tumorigenesis by largely elusive mechanisms. Investigating the consequences of Early mitotic inhibitor 1 (Emi1) depletion in human cells, previously associated with rereplication, we show by DNA fiber labeling that origin reactivation occurs rapidly, well before accumulation of cells with >4N DNA, and is associated with checkpoint-blind ssDNA gaps and replication fork reversal. Massive RPA chromatin loading, formation of small chromosomal fragments, and checkpoint activation occur only later, once cells complete bulk DNA replication. We propose that deregulated origin firing leads to undetected discontinuities on newly replicated DNA, which ultimately cause breakage of rereplicating forks.

    Original languageEnglish
    Pages (from-to)2537-2542
    Number of pages6
    JournalGenes and Development
    Volume27
    Issue number23
    DOIs
    Publication statusPublished - 1 Dec 2013

    Keywords

    • DNA replication
    • Genome integrity
    • Origin licensing
    • Rereplication
    • Tumorigenesis

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    Neelsen, K. J., Zanini, I. M. Y., Mijic, S., Herrador, R., Zellweger, R., Chaudhuri, A. R., Creavin, K., Blow, J. J., & Lopes, M. (2013). Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes and Development, 27(23), 2537-2542. https://doi.org/10.1101/gad.226373.113