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

被引：72

作者：

Neelsen, Kai J. ^{[1
]}

Zanini, Isabella M. Y. ^{[1
]}

Mijic, Sofija ^{[1
]}

Herrador, Raquel ^{[1
]}

Zellweger, Ralph ^{[1
]}

Chaudhuri, Arnab Ray ^{[1
]}

Creavin, Kevin D. ^{[2
]}

Blow, J. Julian ^{[2
]}

Lopes, Massimo ^{[1
]}

机构：

[1] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland

[2] Univ Dundee, Ctr Gene Regulat & Express, Dundee DD1 5EH, Scotland

来源：

GENES & DEVELOPMENT | 2013年 / 27卷 / 23期

基金：

瑞士国家科学基金会; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

DNA replication; genome integrity; origin licensing; rereplication; tumorigenesis; RE-REPLICATION; CDT1; DEGRADATION; GEMININ BINDING; ACTIVATION; MECHANISMS; COMPLEX; CANCER; CELLS; EMI1; UBIQUITINATION;

D O I：

10.1101/gad.226373.113

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2537 / 2542

页数：6

共 33 条

[1] PCNA functions as a molecular platform to trigger Cdt1 destruction and prevent re-replication [J].