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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; Ray Chaudhuri, Arnab; Creavin, Kevin D; Blow, J Julian; Lopes, Massimo (2013). Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes and Development, 27(23):2537-2542.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:06 Dec 2013 11:43
Last Modified:05 Apr 2016 17:13
Publisher:Cold Spring Harbor Laboratory Press
ISSN:0890-9369
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1101/gad.226373.113
PubMed ID:24298053

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