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

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Mol Cell. 2009 Jul 31;35(2):228-39.

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

Mediate Genome Stability.

sen RD, Soni DV, Wollman R, Hahn AT, Yee MC, Guan A, Hesley JA, SC,

Cromwell EF, Solow-Cordero DE, Meyer T, Cimprich KA.

Department of Chemical and Systems Biology, Stanford University, Stanford, CA

94305, USA.

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 downregulation led to elevated levels of

H2AX phosphorylation (gammaH2AX) 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 gammaH2AX 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.