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

Neelsen, Kai J., Zanini, Isabella M. Y., Mijic, Sofija, Herrador, Raquel, Zellweger, Ralph, Chaudhuri, Arnab Ray, Creavin, Kevin, Blow, J. Julian ORCID: https://orcid.org/0000-0002-9524-5849 and Lopes, Massimo (2013) Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes and Development, 27 (23). pp. 2537-2542. ISSN 0890-9369

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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.

Item Type:	Article
Additional Information:	© 2013 Neelsen et al.; Published by Cold Spring Harbor Laboratory Press. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.
Uncontrolled Keywords:	dna replication,genome integrity,origin licensing,rereplication,tumorigenesis
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Depositing User:	LivePure Connector
Date Deposited:	10 Jun 2024 10:32
Last Modified:	25 Sep 2024 17:51
URI:	https://ueaeprints.uea.ac.uk/id/eprint/95446
DOI:	10.1101/gad.226373.113

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