A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response

Britt Adamson, Agata Smogorzewska, Frederic D. Sigoillot, Randall W. King, Stephen J. Elledge

Research output: Contribution to journalArticle

225 Scopus citations

Abstract

Repair of DNA double-strand breaks is critical to genomic stability and the prevention of developmental disorders and cancer. A central pathway for this repair is homologous recombination (HR). Most knowledge of HR is derived from work in prokaryotic and eukaryotic model organisms. We carried out a genome-wide siRNA-based screen in human cells. Among positive regulators of HR we identified networks of DNA-damage-response and pre-mRNA-processing proteins, and among negative regulators we identified a phosphatase network. Three candidate proteins localized to DNA lesions, including RBMX, a heterogeneous nuclear ribonucleoprotein that has a role in alternative splicing. RBMX accumulated at DNA lesions through multiple domains in a poly(ADP-ribose) polymerase 1-dependent manner and promoted HR by facilitating proper BRCA2 expression. Our screen also revealed that off-target depletion of RAD51 is a common source of RNAi false positives, raising a cautionary note for siRNA screens and RNAi-based studies of HR.

Original languageEnglish (US)
Pages (from-to)318-328
Number of pages11
JournalNature cell biology
Volume14
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

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