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Title

BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2

AuthorsBhatia, Vaibhav; Barroso, Sonia ; García-Rubio, María L. ; Tumini, Emanuela ; Herrera-Moyano, Emilia ; Aguilera, Andrés
KeywordsDouble-strand DNA breaks
Breast cancer
RNA transport
Issue Date1-Jun-2014
PublisherNature Publishing Group
CitationNature 511(7509): 362-365 (2014)
AbstractGenome instability is central to ageing, cancer and other diseases. Itis not only proteins involved in DNA replication or the DNA damage response (DDR) that are important for maintaining genome integrity: from yeast to higher eukaryotes,mutationsin genesinvolved in pre-mRNA splicing andin the biogenesis and export ofmessenger ribonucleoprotein (mRNP) also induce DNA damage and genome instability. This instability is frequently mediated by R-loops formed by DNA–RNA hybrids and a displaced single-stranded DNA1 . Here we show that the human TREX-2 complex,whichisinvolvedinmRNP biogenesis and export, prevents genome instability as determined by the accumulation of c-H2AX (Ser-139 phosphorylated histone H2AX) and 53BP1 foci and single-cell electrophoresisin cells depleted of the TREX-2 subunits PCID2, GANP and DSS1.We show that the BRCA2 repair factor,which binds to DSS1, also associateswith PCID2 in the cell. The use of an enhanced green fluorescent protein-tagged hybrid-binding domain of RNase H1 and the S9.6 antibody did not detect R-loopsin TREX-2-depleted cells, but did detect the accumulation of R-loops in BRCA2-depleted cells. The results indicate that R-loops are frequently formed in cells and that BRCA2 is required for their processing. 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
Publisher version (URL)http://dx.doi.org/10.1038/nature13374
URIhttp://hdl.handle.net/10261/121603
DOI10.1038/nature13374
ISSN0028-0836
E-ISSN1476-4687
Appears in Collections:(CABIMER) Artículos
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