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

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...

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Bibliographic Details
Published in:Genes & development Vol. 27; no. 23; p. 2537
Main Authors: Neelsen, Kai J, Zanini, Isabella M Y, Mijic, Sofija, Herrador, Raquel, Zellweger, Ralph, Ray Chaudhuri, Arnab, Creavin, Kevin D, Blow, J Julian, Lopes, Massimo
Format: Journal Article
Language:English
Published: United States 01.12.2013
Subjects:
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
Chromosome Breakage
DNA - biosynthesis
DNA Replication - genetics
F-Box Proteins - genetics
F-Box Proteins - metabolism
Humans
Replication Origin - genetics
RNA, Small Interfering - metabolism
Templates, Genetic
origin licensing
DNA replication
rereplication
tumorigenesis
genome integrity
ISSN:1549-5477, 1549-5477
Online Access:Get more information
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Summary: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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content type line 23
ISSN:1549-5477
1549-5477
DOI:10.1101/gad.226373.113