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Sequence of the FRA3B Common Fragile Region: Implications for the Mechanism of FHIT Deletion

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Sequence of the FRA3B Common Fragile Region: Implications for the Mechanism of FHIT Deletion Proc. Natl. Acad. Sci. USA Vol. 94, pp. 14584–14589, December 1997 Genetics Sequence of the FRA3B common fragile region: Implications for the mechanism of FHIT deletion HIROSHI INOUE,HIDESHI ISHII,HANSJUERG ALDER,ERIC SNYDER,TERESA DRUCK,KAY HUEBNER, AND CARLO M. CROCE Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, PA 19107 Communicated by Sidney Weinhouse, Jefferson Medical College, Philadelphia, PA, October 30, 1997 (received for review October 3, 1997) ABSTRACT The hypothesis that chromosomal fragile sites sequence (17), resulting in a total sequenced region of 276 kbp. may be ‘‘weak links’’ that result in hot spots for cancer-specific This region also showed hemizygous loss in numerous cancers chromosome rearrangements was supported by the discovery (19, 26–31). We also sequenced a region encompassing the that numerous cancer cell homozygous deletions and a familial familial kidney cancer-associated translocation (32) break be- translocation map within the FHIT gene, which encompasses the tween FHIT exons 3 and 4. common fragile site, FRA3B. Sequence analysis of 276 kb of the FRA3ByFHIT locus and 22 associated cancer cell deletion end- MATERIALS AND METHODS points shows that this locus is a frequent target of homologous DNA Sequencing Templates. As shown in Fig. 1, six over- recombination between long interspersed nuclear element se- lapping cosmid clones, covering '200 kbp of the FHIT locus quences resulting in FHIT gene internal deletions, probably as a from intron 4 through a large part of intron 5 (16), were result of carcinogen-induced damage at FRA3B fragile sites. sequenced completely. BAC clones 1O12 and 358N7, overlap- ping the centromeric and telomeric ends of the cosmid contig, Fragile sites are chromosome regions that reveal cytogeneti- were obtained from Research Genetics, Huntsville, AL. For cally detectable gaps after the exposure of cells to specific sequencing the t(3;8) translocation region, a bacteriophage reagents (1); several folate-sensitive, heritable fragile sites clone from a YAC 850A6 phage library was selected by using have been localized to unstable CGG repeats, and one of these the D3S1480 amplified product. Phage ends were sequenced, sites, the FRA11B at 11q23.3, is associated with Jacobsen and primers pairs prepared. PCR amplification of hybrid (11q-) syndrome that shows a direct link between a fragile site DNAs, including DNA from a hybrid carrying the der 3 and in vivo chromosome breakage (2). Another heritable chromosome from a t(3;8) family member, showed that this fragile site, the distamycin-A sensitive FRA16B, recently was phage spanned the break, as did an 8.4-kb subclone (33). found to be caused by an expanded 33-bp AT-rich minisatellite Cell Lines. Cancer cell lines KATO III (stomach carcinoma), repeat (3). Thus, repeat expansion is a property of trinucle- MDA-MB436 (breast carcinoma), LoVo (colon adenocarci- otide and minisatellite repeats, and these dynamic mutations noma), and LS180 (colon adenocarcinoma) were obtained are sometimes detected as fragile sites. from the American Type Culture Collection and HK1 (naso- After induction of fragile sites in somatic cell hybrids, pharyngeal carcinoma) was provided by Dolly Huang (Chinese increased frequencies of translocations, deletions (4–6), and University of Hong Kong). Deletion in the FHIT locus and plasmid DNA integration (7) at fragile sites have been ob- absence of Fhit protein were reported for these cell lines (16, served. Also, because the chromosomal positions of fragile 19, 20). sites apparently coincide cytogenetically with the regions of Shotgun Sequencing. Cosmid and BAC DNA were prepared similar chromosomal aberrations in cancer cells, it has been by Qiagen Mini or Maxi prep kit (Qiagen, Chatsworth, CA). For postulated that fragile sites, which are susceptible to carcino- each clone, 30-ml aliquots (30 mg) of DNA were sonicated at the gen-induced alterations (8), could play a role in cancer cell- lowest energy setting for 5–10 sec at 0°C with the 3-mm probe. specific chromosomal rearrangements (9–12), but the direct Aliquots were electrophoresed on 0.8% agarose gels, and the proof of involvement of fragile sites in cancer has been lacking. preparations for which the peak fragment size was 2–3 kb were Recently, the most inducible common fragile site, FRA3B at analyzed further. DNA fragments (50 ml) for each clone were 3p14.2, was shown to exhibit gaps or fragility over a broad region digested for 10 min at 30°C with BAL-31 nuclease (New England (13–15), much of which has been cloned (7, 13, 14, 16, 17) and Biolabs), extracted with phenol, precipitated, dissolved, and partially sequenced (7, 14, 17, 18). A papillomavirus insertion site fractionated on a 0.8% low melting agarose gel. The 1.5- to 2.0-kb (14), plasmid integration sites (7), and cancer specific transloca- fraction was excised, extracted with glassmilk with a Geneclean tions and deletions (17, 19, 20) have been mapped within the III kit (Bio 101), and dissolved in 10 ml of distilled water. DNA FHIT gene, which encompasses FRA3B (16). FHIT alleles are concentration was measured with Picogreen fluorescent dye frequently inactivated in common human cancers (16, 20–24), (Molecular Probes) on a FluorImager SI (Molecular Dynamics). and the replacement of Fhit expression in cancer cells suppresses A two-step ligation procedure was used to produce plasmid their tumorigenicity (25). Thus, chromosome rearrangement at libraries essentially as described previously (34), for each cosmid FRA3B, probably following carcinogen damage, is associated or BAC clone. Recombinant plasmids were isolated by Qiagen with development of major human cancers. BioRobot 9600, and DNA concentration measured on the Fluo- To elucidate mechanisms involved in FHIT alterations and rImager SI analyzer. Plasmid DNAs were digested with EcoRI FRA3ByFHIT fragility, we sequenced a '200-kb region sur- and HindIII (Boehringer Mannheim) and were gel separated to rounding FHIT exon 5, which included the majority of induced confirm the presence of insert DNA. Sequencing reactions and gaps (15) and overlaps the reported 110-kb partial intron 4 analysis were performed by using dyedeoxy-terminator reaction The publication costs of this article were defrayed in part by page charge Abbreviations: RT, reverse transcription; LINE, long interspersed payment. This article must therefore be hereby marked ‘‘advertisement’’ in nuclear element. accordance with 18 U.S.C. §1734 solely to indicate this fact. Data deposition: The sequences reported in this paper have been © 1997 by The National Academy of Sciences 0027-8424y97y9414584-6$2.00y0 deposited in the GenBank database (accession nos. AF020503, PNAS is available online at http:yywww.pnas.org. AF020504, AF020609-AF020615, and AF019967). 14584 Downloaded by guest on September 25, 2021 Genetics: Inoue et al. Proc. Natl. Acad. Sci. USA 94 (1997) 14585 Reverse Transcription–PCR (RT-PCR) and cDNA Library Screening. RT-PCR was performed by using primers Z13– 44yf(59-GTCCGTAGATCTTGTTATGG-39) and Z13–44yr (59-TGGCTTTCAGGCATGTTGAGC-39) and fetal kidney cDNA. A fetal kidney cDNA library was purchased (CLON- TECH) and 33 106 plaques were screened. Inverse PCR. Inverse PCR amplifications were performed by using a modification of the method described in ref. 40. DNA (3 mg) was digested with 50 units of restriction enzymes with four or five base pair recognition sites. The incompatible cohesive ends were filled in with T4 DNA polymerase. For y FIG. 1. The normal FHIT FRA3B locus. The top line represents circularization, the digested DNA was ligated in a 50-ml the locus with positions of reported markers and FHIT exons. The long reaction with 4 units of T4 DNA ligase and ligation buffer (50 hatched bar represents the 210-kb sequenced region, which overlapped z y y the reported U66722 sequence (solid bar) (17). Genomic YAC, BAC, mM Tris Cl, pH 7.4 10 mM MgCl2 10 mM ATP) at 16°C phage and cosmid clones used in the analysis are shown. The small overnight. Circular products served as PCR templates under hatched bar represents the sequence of chromosome 3 at the t(3;8) the following conditions: 5 min at 95°C followed with 35 cycles break. of 15 sec at 95°C, 30 sec at 60°C (first 10 cycles), 59°C (second 10 cycles), and 58°C (last 15 cycles), and then 3 min at 72°C. chemistry on a Perkin–ElmeryCetus DNA Thermal Cycler 9600 and the Applied Biosystems Model 377 DNA sequencing systems. RESULTS Sequence data were edited, assembled, and analyzed with DNA Sequence Analysis. Shotgun sequencing was performed the SEQUENCHER 3.0 program (Gene Codes, Ann Arbor, MI). for the 210-kb region encompassing FHIT exon 5; 1,427,400 bp Strategies implemented for sequence completion included were sequenced for a coverage ratio of 6.9. Sequence fidelity was primer walking to extend the sequence read of a given sub- confirmed by primer walking, by amplification of identical se- clone, to close a gap or confirm sequence that was obtained in quence fragments from human DNA templates and by using the opposite orientation. The sequence of the regions not Southern blot detection of expected size fragments in human covered at least twice in one orientation and once in the other DNAs. The complete sequence, numbered through 206,881 be- was obtained by PCR amplification and sequencing of the ginning at the telomeric end, was submitted to GenBank (acces- sion no. AF020503). Fig. 1 shows the location of the sequenced region from a cosmid or plasmid clone. After proofreading, the region relative to FRA3ByFHIT landmarks. The GC content of the final sequence was analyzed with BLAST (35), REPEATMASKER 210-kb region was 38.39 6 0.50% with minimal deviation from this (36), GRAIL II (37), GENEFINDER (FGENEH) (38), and GENE- mean over the region, as shown for the 30-kb subregions in Table SCAN (39) programs available at http:yygc.bcm.tmc.edu: 8088y y 1; this value was similar to that of the adjacent 110-kb sequence search-launcher launcher.html.
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