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

Abstract

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5′ end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development.

Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas

“…The precise molecular mechanisms by which R-loops promote tumorigenesis remain unclear. A genome-wide examination of R-loop dynamics in different cell types from BRCA1 mutation carriers revealed BRCA1 -mutation-associated R-loops preferentially accumulate in luminal epithelial cells and at specific genomic loci leading to tumorigenesis (Zhang et al, 2017). Furthermore, in BRCA1 -deficient carcinomas, there is a significant enrichment of mutations at precise locations where BRCA1 is predicted to suppress R-loops (Hatchi et al, 2015).…”

Mammary stem cells and progenitors: targeting the roots of breast cancer for prevention

“…Along the same lines, molecular profiling indicates that luminal progenitors are cells with active transcription. A higher accumulation of R‐loops, which naturally occur as by‐products of transcription, was noted in luminal progenitors compared to basal cells (Zhang et al , ). This is relevant since luminal progenitors are the likely cell‐of‐origin for BRCA1‐mutated breast cancer, and the dysregulated levels of R‐loops seen in cancers lead to genomic instability (Aguilera & García‐Muse, ).…”

The INO80 ATP-dependent chromatin remodelling complex alleviates stalled Polymerase II to promote non-coding RNA transcription termination

“…Uncontrolled transcription elongation and dysregulated RNAPII pausing have been implicated in human disease (Rahl et al, 2010;Zhang et al, 2017b). Mutations in the RNA surveillance machinery have been associated with increased transcriptional stress and genomic instability (Aguilera and Gomez-Gonzalez, 2008), both hallmarks of cancer (Kotsantis et al, 2018).…”