The common fragile site FRA16D and its associated gene WWOX are highly conserved in the mouse at Fra8E1

Abstract

Recently, several common fragile sites (CFSs) have been cloned and characterized, including the two most frequently observed in the human population, FRA3B and FRA16D. In addition to their high frequency of breakage, FRA3B and FRA16D colocalize with genes crossing large regions of breakage. At FRA3B, the fragile histidine triad (FHIT) gene spans more than 1 Mb, and at FRA16D, the WWOX gene spans more than 750 kb. It has also been shown that in Mus musculus, a CFS Fra14A2 and the mouse Fhit gene are conserved in the orthologous region of the genome. In this study, we positioned the ortholog to WWOX (Wox1) at chromosome band 8E1 in the mouse genome. To determine whether, like Fra14A2 and Fhit, Fra8E1 and Wox1 colocalized in the mouse, we prepared bacterial and yeast artificial chromosome probes, and we hybridized them to aphidicolin-treated mouse metaphase chromosomes. Our data demonstrate that Wox1 colocalizes with Fra8E1. Furthermore, the sequence from this region, including introns, is highly conserved over at least a 100-kb region. This evolutionary conservation suggests that the two most active CFSs share many features, and that CFSs and their associated genes may be necessary for cell survival.

FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila

“…This is further supported by other striking similarities between the WWOX and FHIT genes. They are both extremely large (>1 Mb in mouse and human), they both are sites of DNA instability in human cancers and their association with fragile sites has been conserved in mouse (Glover et al, 1998;Krummel et al, 2002). These features are also shared by the Parkin, gene which maps to FRA6E (Cesari et al, 2003;Denison et al, 2003;Picchio et al, 2004;Wang et al, 2004) and the ionotropic glutamate receptor delta 2 (GRID2) gene, which maps to FRA4F (Bluteau et al, 2002;Rozier et al, 2004).…”

Alterations in the common fragile site gene Parkin in ovarian and other cancers

“…FRA3B and FRA16D also appear to be highly conserved between humans and mice. Both FRA3B and FRA16D represent fragile regions in the mouse, Fra14A2 and Fra8E1, respectively (Shiraishi et al, 2001;Krummel et al, 2002). Additionally, the mouse orthologs of FHIT and WWOX (Fhit and Wox1) also appear to have been conserved together through evolution (Shiraishi et al, 2001;Krummel et al, 2002).…”

“…Both FRA3B and FRA16D represent fragile regions in the mouse, Fra14A2 and Fra8E1, respectively (Shiraishi et al, 2001;Krummel et al, 2002). Additionally, the mouse orthologs of FHIT and WWOX (Fhit and Wox1) also appear to have been conserved together through evolution (Shiraishi et al, 2001;Krummel et al, 2002). The FRAXB region is distinct from the other three highly active CFS regions, as instability within this CFS region extends for only 500 kb (Arlt et al, 2002).…”

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

“…In addition, the chromosomal regions spanning these large genes in the mouse are also CFSs (Krummel et al, 2002;Matsuyama et al, 2003); thus, the large genes and highly unstable regions are co-conserved, suggesting that together they serve some important cellular function. As the CFS regions and the large size CFS genes were associated with human cancer development, we began to systematically test a number of large genes that were derived from chromosomal regions known to contain a CFS.…”