RORA, a large common fragile site gene, is involved in cellular stress response

Abstract

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 700 kb to over 1.5 Mb 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 730 kb 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.

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

“…A plausible candidate that fits this criterion is the RORa1-binding site in the positive regulatory region of the LIMK2b promoter (Nomoto et al, 1999). In support, RORa mRNA is often downregulated in tumor cell lines and cancers (Zhu et al, 2006;Lu et al, 2007;Jetten 2009), and its expression is upregulated by a variety of genotoxic stresses (Zhu et al, 2006). Whether this latter function also includes coactivation with p53, for example, in the transactivation of LIMK2b, remains to be determined.…”

Genetic or epigenetic silencing of low density lipoprotein receptor‐related protein 1B expression in oral squamous cell carcinoma

“…Furthermore, two large CFS genes, GRID2 and RORA, have recently been proposed as candidate tumor suppressors, residing within the unstable and evolutionally conserved chromosomal regions 4q22 and 15q22.2 (FRA15A), respectively. (30,31) LRP1B is also a very large gene, containing 92 exons and spanning 1.9 Mb of genomic sequence within FRA2F (2q22.1, http://www.ncbi.nlm.nih.gov/). (17) Inactivation of this gene due to homozygous deletions or epigenetic events has been reported in various cancers (19)(20)(21)(22) and by us in ESCC.…”

Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones

“…According to Hecht et al (4) and others we prefer a classification of high and low frequency FS. In order to prevent double naming of FS in the same cytogenetic location, caused historically by different modes of induction, an expanded definition of FS into fragile regions is helpful as it becomes more and more clear from molecular mapping data that especially aphidicolin inducible FS do not break at defined sequences but in breakage-prone regions up to 10 Mb (35,36) where the break is most likely to appear.…”