A fragile site in the human U2 small nuclear RNA gene cluster is revealed by adenovirus type 12 infection.

Abstract

Using in situ hybridization, we found that the U2 small nuclear RNA gene cluster mapped very close to and was frequently disrupted by the gaps and breaks induced specifically in the human 17q21-q22 region by highly oncogenic adenovirus type 12 (Adl2). Restriction mapping revealed no structural alterations in the U2 gene locus as a result of Adl2 infection. Likewise, no Adl2-induced alterations in U2 RNA levels were detected. We estimate that the maximum size of the region specifically disrupted by this virus was less than 350 to 700 kilobases. A comparison of these data with similar data regarding biochemically induced fragile sites was made.

FRA7G extends over a broad region: coincidence of human endogenous retroviral sequences (HERV-H) and small polydispersed circular DNAs (spcDNA) and fragile sites

“…Although there are likely to be many dierent causes of chromosomal fragility, it has been shown in at least one case that a fragile site can correspond to a region of incompletely condensed chromatin (Durnam et al, 1986). Agents that result in incomplete condensation in speci®c chromosomal regions could potentially explain why fragile sites are genetically recombinogenic and why certain fragile sites serve as preferential targets for viral or plasmid integration (Rassool et al, 1991;Smith et al, 1992;van der Drift et al, 1994).…”

The Transcriptionally Competent U2 Gene Is Necessary and Sufficient for Adenovirus Type 12 Induction of the Fragile Site at 17q21-22

“…An additional shared feature of Ad12 modification sites is their proximity to or coincidence with gene clusters for structural RNAs: U2 small nuclear RNA at the 17q21-22 site and U1 genes or pseudogenes and 5S rRNA genes at 1p36, 1q21, and 1q42-43, respectively (11,19,20,25,32). Sensitivity to the virus varies among these sites, with the one at 17q21-22 being the most sensitive (8,23,30,33,39). We have exploited this viral system to investigate the mode of induction of chromosome fragility and to define the genomic sequences which are the target of this process.…”

“…Exceptions include the fragile site FRAXA, for which expansion and methylation of a trinucleotide repeat and delayed replication have been implicated in fragility of the FMR1 locus in individuals affected with fragile X syndrome (12). Recent data have shown that the same mechanism is responsible for fragility at three other sites: FRAXE, FRAXF, and FRA16A (15,24,27).Oncogenic adenoviruses, such as adenovirus type 12 (Ad12), are capable of inducing fragility at four chromosomal regions, referred to as Ad12 modification sites (8,23,30,33,39). This effect does not depend upon integration of the viral genome (8) but requires expression of viral proteins (30).…”

“…This effect does not depend upon integration of the viral genome (8) but requires expression of viral proteins (30). On the basis of their cytogenetic appearance (uncoiled chromatin and heterochromatic gaps) and their map location at or near sites frequently rearranged in human cancer, Ad12 modification sites are likely to represent true fragile sites (5,8,23,30,33,39). Indeed, Ad12 sites are also sensitive to drugs which induce common fragile sites (5, 38).…”

“…Oncogenic adenoviruses, such as adenovirus type 12 (Ad12), are capable of inducing fragility at four chromosomal regions, referred to as Ad12 modification sites (8,23,30,33,39). This effect does not depend upon integration of the viral genome (8) but requires expression of viral proteins (30).…”