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Cold Spring Harbor Laboratory Press, Genes & Development, 23(27), p. 2537-2542, 2013

DOI: 10.1101/gad.226373.113

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

Journal article published in 2013 by Kai J. Neelsen, Isabella M. Y. Zanini, Sofija Mijic ORCID, Raquel Herrador, Ralph Zellweger, Arnab Ray Chaudhuri, Arnab Ray Chaudhuri, Kevin D. Creavin, J. Julian Blow, J. Julian Blow ORCID, Massimo Lopes ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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. © 2013 Neelsen et al.