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Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

ABSTRACT: Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in DNA repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. Cell culture-based studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcriptional regulation and genetic instability. We found that BRCA1 mutation-associated R-loop accumulates preferentially in luminal epithelial cells of cancer-free human breast tissue, and at the 5' end of those genes that experience promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of mouse NELF-B/COBRA1, a Pol II-pausing factor and BRCA1-binding protein, in Brca1 knockout mouse mammary epithelium ameliorates R-loop accumulation and reduces mammary tumorigenesis. Our studies show that Pol II pausing is a previously unappreciated contributor to BRCA1-associated R-loop accumulation and breast cancer development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96672 | GEO | 2017/06/27

SECONDARY ACCESSION(S): PRJNA379324

REPOSITORIES: GEO

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Homo sapiens

Project description:Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

| PRJNA379324 | ENA

RNA Polymerase II Pausing Can Be Retained or Acquired During Activation of Genes Involved in the Epithelial to Mesenchymal Transition

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