Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

Abstract

Fragile sites are classified as common or rare depending on their occurrence in the populations. While rare sites are mainly associated with inherited diseases, common sites have been involved in somatic rearrangements found in the chromosomes of cancer cells. Here we study a mouse locus containing the ionotropic glutamate receptor delta 2 (grid2) gene in which spontaneous chromosome rearrangements occur frequently, giving rise to mutant animals in inbred populations. We identify and clone common fragile sites overlapping the mouse grid2 gene and its human ortholog GRID2, lying respectively at bands 6C1 and 4q22 in a 7-Mb-long region of synteny. These results show a third example of orthologous common sites conserved at the molecular level, and reveal an unexpected link between an inherited disease and an aphidicolin-sensitive region. Recurrent deletions of subregions of band 4q22 have been previously described in human hepatocellular carcinomas. This 15-Mb-long region appears precisely centered on the site described here, which strongly suggests that it also plays a specific role in hepatic carcinogenesis.

SNCA locus duplication carriers: from genetics to Parkinson disease phenotypes

“…In the duplicated locus, we identified a >750 pb length homology sequence between L1PA2 and L1PA4 with several perfect sequence matches; which is a required condition to generate NAHR (Inoue & Lupski, 2002;Conrad et al, 2009). Moreover, this region of chromosome 4q21 has a high DNA flexibility and A/T-content probably which is suspected to promote the occurrence of fragile sites (Rozier et al, 2004). Taken as a whole, these data strengthen the idea that homologous recombination has preferred positions and architectural DNA characteristics, since rearrangement breakpoints are associated with LCRs more frequently that would be expected by chance alone (Shaw et al, 2004).…”

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

“…3). Additionally, 52 identified and in parts mapped FS were already published, but not included in the current genome browser versions (13,14,15,16,17,19,23,34). Most of these sites were confirmed in this study which underlines their eligibility to be appreciated as FS.…”

“…Additionally, differences in the observable FS-frequency within different individuals are well known (11,12). Besides these 88 official, database-annotated common FS others were observed and reported, including six recently reported new sites, particularly FRA4F (13), FRA7K (14), FRA6H (15), FRA9G (16), FRA13E (15) and FRA18C (17).…”

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

“…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). These properties appear to have been acquired quite independently during evolution as the genes themselves bear no DNA sequence similarity nor are their encoded proteins members of the same protein superfamily.…”