BRCA2 Inhibits Genome Instability by Preventing R-Loop Accumulation

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Genome instability and DNA damage in cancer can be induced by mutations in genes involved in pre-mRNA splicing and biogenesis and export of messenger ribonucleoprotein (mRNP). Instability can be mediated by R-loops formed by DNA-RNA hybrids and displaced single-stranded DNA.

The TREX-2 complex is involved in mRNP biogenesis and export. In a study reported in Nature, Bhatia and colleagues found that the TREX-2 complex acts to prevent genome instability as shown by accumulation of γ-H2AX and 53BP1 foci as well as by single-cell electrophoresis in cells depleted of the TREX-2 subunits PCID2, GANP, and DSS1.

The investigators showed that BRCA2 repair factor binds to DSS1 and also associates with PCID2 within cells. Whereas R-loops were not detected in TREX-2–depleted cells, they were observed to accumulate in BRCA2-depleted cells. The findings indicate both that R-loops are frequently formed in cells and that BRCA2 is required for their processing.

The investigators concluded, “This link between BRCA2 and RNA-mediated genome instability indicates that R-loops may be a chief source of replication stress and cancer-associated instability.” ■

Bhatia V, et al: Nature 511:362-365, 2014.