![]() ![]() Sen1, the SETX yeast homolog, was shown to contribute to the processing of various RNA species and to the distribution of RNA polymerase II (RNAPII) across the genome ( Mischo et al., 2011, Steinmetz et al., 2006, Ursic et al., 1997). Disruption of the Setx gene in mice leads to a defect in spermatogenesis, caused by failure of meiotic recombination ( Becherel et al., 2013). Our laboratory has identified senataxin (SETX) as a putative BRCA1 binding partner in a yeast two hybrid and several, independent TAP-MS-based genome-wide BRCA1/protein interaction screens ( Hill et al., 2014 and D.M.L., unpublished data). Therefore, identifying new BRCA1 binding partners and their associated functions may yield valuable insights. However, in the absence of a coherent underlying mechanism, there is still no definitive evidence of which specific BRCA1 functions are required for breast and ovarian cancer suppression ( Huen et al., 2010, Venkitaraman, 2014). Many of these BRCA1 properties and, in particular, those that protect genome integrity, probably contribute to its tumor suppressing function ( Silver and Livingston, 2012, Tutt and Ashworth, 2002). As part of several complexes, BRCA1 contributes to double-strand DNA break (DSB) repair by homologous recombination (HR), stalled fork repair, cell-cycle checkpoint activation, transcription regulation, heterochromatin maintenance, mitotic spindle formation, RNA splicing control, and estrogen metabolism ( Gardini et al., 2014, Gorski et al., 2011, Mullan et al., 2006, Pathania et al., 2011, Savage et al., 2014a, Savage et al., 2014b, Venkitaraman, 2014, Zhu et al., 2011). Since its discovery, researchers have intensively investigated the mechanisms by which full-length BRCA1 (p220) functions as a tumor suppressor.īRCA1 is engaged in numerous direct and indirect physical interactions with specific partner proteins ( Huen et al., 2010). Germline mutations of the breast cancer susceptibility gene 1 ( BRCA1) significantly increase the risk of developing breast and ovarian cancers ( Tutt and Ashworth, 2002). Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites. ![]() 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. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. 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. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. We do our best to visually represent all the shades on the website and we do provide approximate RGB values, but pictures may vary slightly from the actual product.The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Therefore our backdrops are not made to exactly match specific color systems, like Pantone or RGB values. NOTE: Our paper is custom made using dyes uniquely for Savage distribution. Savage Seamless Paper is acid-free, lignin free and pH neutral. Take your small and large-scale crafting, art and visual design projects to the next level with your next roll of seamless paper. Being a cost-effective and versatile material, Savage Seamless Paper is not limited to just photographic use. ![]() ![]() With sizes spanning up to 50 yards of paper length, just roll out what you need and trim the end when finished, to guarantee a fresh and sleek background with each use. Seamless Paper provides a high-quality, non-reflecting surface with an exquisite, fine-tooth feel that’s ideal for creating smooth and even backgrounds in portraits, commercial photography, product photography, videography, and much more. ![]()
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