Human Molecular Genetics, Vol 5, 187-195, Copyright © 1996 by Oxford University Press
CM Wilke, BK Hall, A Hoge, W Paradee, DI Smith and TW Glover
The common fragile site at 3p14.2 (FRA3B) is the most sensitive site on
normal human chromosomes for the formation of gaps and breaks when DNA
replication is perturbed by aphidicolin or folate stress. Although rare
fragile sites are known to arise through the expansion of CCG repeats, the
mechanism responsible for common fragile sites is unknown. Beyond being a
basic component of chromosome structure, no biological effects of common
fragile sites have been convincingly shown, although suggestions have been
made that breakage and recombination at these sites may sometimes be
mechanistically involved in deletions observed in many tumors and in
constitutional deletions. In an observation related to the high rate of
recombination at fragile sites, a number of studies have shown a
statistical association between the integration of transforming DNA viruses
and chromosomal fragile sites. Using FISH analysis we recently identified a
1.3 Mb YAC spanning both FRA3B and the t(3;8) translocation associated with
hereditary RCC. Here we report the further localization of FRA3B within
this YAC. Using lambda subclones of the YAC as FISH probes, gaps and breaks
were found to occur over a broad region of at least 50 kb. Neither CCG nor
CAG repeats were found in this region suggesting a different mechanism for
fragility than seen with rare fragile sites. We further show that an area
of frequent gaps and breaks within FRA3B, defined by a lambda contig,
coincides with a previously characterized site of HPV16 integration in a
primary cervical carcinoma. The HPV16 integration event gave rise to a
short chromosomal deletion limited to the local FRA3B region within 3p14.2.
Interestingly, 3p14.2 lies within the smallest commonly deleted region of
3p in cervical cancers, which are often HPV16 associated. To our knowledge
this is the first molecular characterization of an in vivo viral
integration event within a confirmed fragile site region, supporting
previous cytogenetic observations linking viral integration sites and
fragile sites.
ARTICLES
FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: direct evidence for the coincidence of viral integration sites and fragile sites
Department of Pediatrics, University of Michigan, Ann Arbor 48109, USA.
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