Deregulated Origin Licensing Leads to Chromosomal Breaks by Rereplication of a Gapped DNA Template

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2013 Dec 4

PMID 24298053

Citations 55

Authors

Kai J Neelsen

Isabella M Y Zanini

Sofija Mijic

Raquel Herrador

Ralph Zellweger

Arnab Ray Chaudhuri

Kevin D Creavin

J Julian Blow

Massimo Lopes

Affiliations

Soon will be listed here.

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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