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

Research output: Contribution to journalArticlepeer-review

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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