BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair.
Mol Cell
; 57(4): 636-647, 2015 Feb 19.
Article
em En
| MEDLINE
| ID: mdl-25699710
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína BRCA1
/
RNA Helicases
/
Reparo do DNA
/
Modelos Genéticos
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article