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Title:
RORA, a large common fragile site gene, is involved in cellular stress response | Oncogene
Description:
Common fragile sites (CFSs) are large genomic regions present in all individuals that are highly unstable and prone to breakage and rearrangement, especially in cancer cells with genomic instability. Eight of the 90 known CFSs have been precisely defined and five of these span genes that extend from 700โkb to over 1.5โMb of genomic sequence. Although these genes reside within some of the most unstable chromosomal regions in the human genome, they are highly conserved evolutionarily. These genes are targets for large chromosomal deletions and rearrangements in cancer and are frequently inactivated in multiple tumor types. There is also an association between these genes and cellular responses to stress. Based upon the association between large genes and CFSs, we began to systematically test other large genes derived from chromosomal regions that were known to contain a CFS. In this study, we demonstrate that the 730โkb retinoic acid receptor-related orphan receptor alpha (RORA) gene is derived from the middle of the FRA15A (15q22.2) CFS. Although this gene is expressed in normal breast, prostate and ovarian epithelium, it is frequently inactivated in cancers that arise from these organs. RORA was previously shown to be involved in the cellular response to hypoxia and here we demonstrate changes in the amount of RORA message produced in cells exposed to a variety of different cellular stresses. Our results demonstrate that RORA is another very large CFS gene that is inactivated in multiple tumors. In addition, RORA appears to play a critical role in responses to cellular stress, lending further support to the idea that the large CFS genes function as part of a highly conserved stress response network that is uniquely susceptible to genomic instability in cancer cells.
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nature portfolio permissions reprints privacy policy nature 379 nature 309 nature advertising arlt mf social media middle springerlink instant access author correspondence personal data data protection permissions nutrient environmental conditions de-lamarter jf multiple tumor types cellular stress response privacy human genome highly conserved evolutionarily cancer genome karyotypes article purchase explore content subscription content large chromosomal deletions european economic area institutional subscriptions read promoter substitutions resulting keck-waggoner cl hooft van huijsduijnen brooks jr bj mayo clinic college article cite trans-acting variants large cfs gene accepting optional cookies rora message produced article zhu journals search log issue learn ludes-meyers jh access renal epithelial cells unstable chromosomal regions usage analysis manage preferences authors contributed equally large genes derived
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