A Genome-wide siRNA Screen Reveals Diverse Cellular Processes and Pathways that Mediate Genome Stability

被引：428

作者：

Paulsen, Renee D.

Soni, Deena V.

Wollman, Roy

Hahn, Angela T.

Yee, Muh-Ching

Guan, Anna

Hesley, Jayne A. ^{[2
]}

Miller, Steven C. ^{[2
]}

Cromwell, Evan F. ^{[2
]}

Solow-Cordero, David E. ^{[1
]}

Meyer, Tobias

Cimprich, Karlene A. ^{[1
]}

机构：

[1] Stanford Univ, Dept Chem & Syst Biol, High Throughput Biosci Ctr, Stanford, CA 94305 USA

[2] MDS Analyt Technol, Sunnyvale, CA 94085 USA

来源：

MOLECULAR CELL | 2009年 / 35卷 / 02期

基金：

美国国家卫生研究院;

关键词：

DNA-DAMAGE-RESPONSE; REPAIR; REPLICATION; GAMMA-H2AX; COMPLEX; PROTEINS; IDENTIFICATION; ACCUMULATION; KINETOCHORES; INSTABILITY;

D O I：

10.1016/j.molcel.2009.06.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Signaling pathways that respond to DNA damage are essential for the maintenance of genome stability and are linked to many diseases, including cancer. Here, a genome-wide siRNA screen was employed to identify additional genes involved in genome stabilization by monitoring phosphorylation of the histone variant H2AX, an early mark of DNA damage. We identified hundreds of genes whose down-regulation led to elevated levels of H2AX phosphorylation (gamma H2AX) and revealed links to cellular complexes and to genes with unclassified functions. We demonstrate a widespread role for mRNA-processing factors in preventing DNA damage, which in some cases is caused by aberrant RNA-DNA structures. Furthermore, we connect increased gamma H2AX levels to the neurological disorder Charcot-Marie-Tooth (CMT) syndrome, and we find a role for several CMT proteins in the DNA-damage response. These data indicate that preservation of genome stability is mediated by a larger network of biological processes than previously appreciated.

引用

页码：228 / 239

页数：12

共 54 条

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