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.
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http://dx.doi.org/10.1038/ncomms15908 | DOI Listing |
Cell Mol Life Sci
December 2024
Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
R-loops, RNA-DNA hybrid structures, are integral to key cellular processes such as transcriptional regulation, DNA replication, and repair. However, aberrant accumulation of R-loops can compromise genomic integrity, leading to the development of various diseases. Emerging evidence underscores the pivotal role of RNA methylation modifications, particularly N6-methyladenosine (mA) and 5-methylcytosine (mC), in orchestrating the formation, resolution, and stabilization of R-loops.
View Article and Find Full Text PDFNature
January 2025
Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Institute of Haematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The maintenance of genomic integrity in rapidly proliferating cells is a substantial challenge during embryonic development. Although numerous cell-intrinsic mechanisms have been revealed, little is known about genome-protective effects and influences of developmental tissue microenvironments on tissue-forming cells. Here we show that fetal liver hepatocytes provide protection to haematopoietic stem and progenitor cell (HSPC) genomes.
View Article and Find Full Text PDFInt J Mol Sci
November 2024
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia.
The mechanism of transcription proceeds through the formation of R-loop structures containing a DNA-RNA heteroduplex and a single-stranded DNA segment that should be placed inside the elongation complex; therefore, these nucleic acid segments are limited in length. The attachment of each nucleotide to the 3' end of an RNA strand requires a repeating cycle of incoming nucleoside triphosphate binding, catalysis, and enzyme translocation. Within these steps of transcription elongation, RNA polymerase sequentially goes through several states and is post-translocated, catalytic, and pre-translocated.
View Article and Find Full Text PDFJ Biol Chem
December 2024
Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas, USA; Materials Science, Engineering, and Commercialization (MSEC) Program, Texas State University, San Marcos, Texas, USA. Electronic address:
Unscheduled R-loops usually cause DNA damage and replication stress, and are therefore a major threat to genome stability. Several RNA processing factors, including the conserved THO complex and its associated RNA and DNA-RNA helicase UAP56, prevent R-loop accumulation in cells. Here, we investigate the function of ALYREF, an RNA export adapter associated with UAP56 and the THO complex, in R-loop regulation.
View Article and Find Full Text PDFCell Rep
November 2024
Department of Pharmacology and Chemical Biology, University of Pittsburgh, UPMC Hillman Cancer, Pittsburgh, PA 15232, USA. Electronic address:
Inactivating mutations in chromatin modifiers, like the α-thalassemia/mental retardation, X-linked (ATRX)-death domain-associated protein (DAXX) chromatin remodeling/histone H3.3 deposition complex, drive the cancer-specific alternative lengthening of telomeres (ALT) pathway. Prior studies revealed that HIRA, another histone H3.
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