Abstract：
:The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent γ-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites.
journal_name
Mol Celljournal_title
Molecular cellauthors
Hatchi E,Skourti-Stathaki K,Ventz S,Pinello L,Yen A,Kamieniarz-Gdula K,Dimitrov S,Pathania S,McKinney KM,Eaton ML,Kellis M,Hill SJ,Parmigiani G,Proudfoot NJ,Livingston DMdoi
10.1016/j.molcel.2015.01.011subject
Has Abstractpub_date
2015-02-19 00:00:00pages
636-647issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(15)00012-Xjournal_volume
57pub_type
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