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[Cancer Research 59, 19-23, January 1, 1999]
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[Cancer Research 59, 19-23, January 1, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Allelic Knockout of Novel Splice Variants of Human Recombination Repair Gene RAD51B in t(12;14) Uterine Leiomyomas1

Eric F. P. M. Schoenmakers2, Christel Huysmans and Wim J. M. Van de Ven

Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven, and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Recently, the high mobility group protein gene HMGIC was identified as the chromosome 12q15 target gene in a variety of benign solid tumors. Here, we report that the recombinational repair gene RAD51B on chromosome 14q23–24 is the preferential translocation partner of HMGIC in uterine leiomyomas. The pathogenetically critical sequences seem to reside in the last coding exon of a novel RAD51B isoform, which encode a domain containing a putative transmembrane anchor and are expressed in the uterus but not in a wide variety of other tissues tested. By fluorescence in situ hybridization, rapid amplification of 3' cDNA ends, and reverse transcription-PCR analysis, we demonstrated consistent chromosomal rearrangements within RAD51B and expression of fusion transcripts, structurally resulting in an allelic knockout of the uterine isoform of RAD51B and confirming a pleiotropic function of this gene.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Uterine leiomyoma is the most common pelvic neoplasm in women, leading to over 200,000 hysterectomies annually in the United States (1 , 2) . A major cytogenetic subgroup among these steroid-dependent tumors is characterized by a t(12;14)(q15;q23–24) (3) . Previously, it was reported that HMGIC, which encodes an architectural transcription factor, is targeted by the chromosome 12q15 aberrations in uterine leiomyomas as well as a variety of other, mostly mesenchymal tumors (4 , 5) . In contrast to the highly variable translocation partners in the latter, uterine leiomyomas almost exclusively use chromosome 14q23–24 as a partner (3) . The chromosome 14 translocation breakpoint cluster region has been studied in more detail (6 , 7) , but the corresponding target gene remains to be identified and the pathogenetic mechanism remains to be characterized. Aiming at the identification of the 14q34–24 pathogenetical sequences, we have now established a YAC3 contig encompassing the chromosome 14 breakpoint cluster region (ULCR14). Subsequent gene identification studies within ULCR14 revealed that RAD51B [Ref. 8 ; also known as R51H2 (9) and hREC2 (10) , a member of the recA/RAD51 recombination repair gene family (11) ] is the chromosome 14 target gene and HMGIC fusion partner in uterine leiomyomas with t(12;14). To map the breakpoints, we defined the genomic organization of the RAD51B gene. Furthermore, we describe the identification of a novel isoform of RAD51B and establish its expression pattern by Northern blot analysis. Finally, to pinpoint the pathogenetically critical sequences, we performed 3'-RACE and RT-PCR analyses and identified and structurally characterized fusion transcripts resulting from the t(12;14)(q15;q23–24) translocations.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
YAC/BAC Contig and Long-Range Physical Map.
YAC clones were isolated from local copies of the Centre d’Étude du Polymorphisme Humain mark 1 and mark 3 YAC libraries. BAC clones were identified on commercially obtained high-density grids (Research Genetics Inc., Huntsville, AL) by colony hybridization. YACs and BACs were further analyzed essentially as described previously (Ref. 4 and references therein).

Generation of YAC- and BAC-derived STSs.
Sequence data from YAC insert ends were obtained using a vectorette-PCR procedure in combination with direct DNA sequencing analysis (4) . Sequence data from BAC insert ends were obtained by direct cycle sequencing using either standard FITC-labeled or Energy Transfer (C-FAM-labeled) T7 and SP6 primers (Amersham Pharmacia Biotech, Roosendaal, the Netherlands). After sequence analysis, specific primer pairs were developed using LASERGENE biocomputing software (DNASTAR, Madison, WI).

PCRs.
PCR amplifications were carried out using a GeneAmp PCR system 2400 or 9600 or a DNA Thermal Cycler (Perkin-Elmer Corp.) in final volumes of 50 µl containing 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, 0.01% gelatin, 2 mM dNTPs, 20 pmol of each oligonucleotide (Eurogentec), 2.5 units of Amplitaq (Perkin-Elmer/Cetus), and 5 ng (for cosmids) to 100 ng (for YAC superpools) of template DNA. For G+C-rich templates, DMSO was added to a final concentration of 10%. After initial denaturation for 5 min at 94°C, 30 amplification cycles were performed, each consisting of denaturation for 10 s at 94°C, annealing for 20 s at the appropriate temperature, and extension for 30 s–1 min at 72°C. The PCR was completed by a final extension at 72°C for 5 min. Results were evaluated by analysis of 10 µl of the reaction product on polyacrylamide minigels.

Cell Culture.
Cell lines containing the classical t(12;14) that were used in this study were established through transfection of primary leiomyoma tumor cells with a construct containing the SV40 early region and have been described previously (4) . Cells were grown in DMEM/F12 supplemented with 10% fetal bovine serum (Life Technologies, Merelbeke, Belgium) and were assayed by standard cytogenetic techniques at regular intervals.

FISH.
Cells of tumor cell lines were arrested in metaphase using colcemid, after which FISH analysis was performed essentially as described previously (4) . Inter-Alu-PCRed YAC DNA or BAC DNA was labeled with either biotin-14-dATP or digoxigenin-11-dUTP (Boehringer, Mannheim, Germany) using the Bionick labeling system (Life Technologies) or the Nick translation system (Life Technologies). The identity of chromosomes was established by simultaneous 4',6-diamidino-2-phenylindole banding. Vectashield antifade medium (Vector Laboratories), containing 4',6-diamidino-2-phenylindole (0.5 g/ml) was added 15 min before slides were analyzed on a Zeiss Axiophot fluorescence microscope equipped with a cooled charged coupled device camera system (Photometrics) using Quips Smart Capture FISH imaging software (Vysis Inc.). Images were printed with a Phaser 440 sublimation printer (Tektronix).

RACE and RT-PCR.
3'-RACE and RT-PCR was performed using part of a modified 3' exon trapping protocol (4) . For first strand cDNA synthesis, nonspecific adapter primer AP2 [5'-AAG GAT CCG TCG ACA TC(T)17-3'] or HMGI-C-specific primer 95C3362 [5'-TAC AGC AGT TTT TCA CTA-3'] was used.

For the specific isolation of 5' sequences of HMGI-C fused to 3' ectopic sequences of RAD51B, the following primer pairs were applied. In the first PCR round, the specific "forward primer" (situated within exon 1 of HMGI-C) 5'-CTT CAG CCC AGG GAC AAC-3' was used, in combination with the "reverse primer" (situated within the last common exon of RAD51B) 5'-TGA AGA ACC AGG CCT TCC-3'. In the second round, the tailed, specific forward primer (nested, as compared to the one used in the first round) 5'-CAU CAU CAU CAU CGC CTC AGA AGA GAG GAC-3' (situated within exon 1 of HMGI-C) was used, in combination with 5'-CUA CUA CUA CUA AGG GGA CTT GGC AAT AAG-3' (situated within the last common exon of RAD51B).

For isolation of possible reciprocal products (5' sequences of RAD51B fused to 3' sequences of HMGI-C), the following primer combinations were used. In the first PCR round, the specific forward primer (situated within the first coding exon of RAD51B) 5'-GGG TAG CAA GAA ACT AAA ACG AGT GGG TT-3' was used, in combination with one of the following reverse primers: 5'-AAA AGA TCC AAC TGC TGC TGA GGT AGA A-3' (situated within the last exon of HMGI-C) or UAP2 (5'-CUA CUA CUA CUA AAG GAT CCG TCG ACA TC-3'). In the second round, the tailed, specific forward primer (nested as compared to the one used in the first round) 5'-CAU CAU CAU CAU TCA CAA GAG CTG TGT GAC CGT CTG-3' (situated within the first coding exon of RAD51B) was used, in combination with either 5'-CUA CUA CUA CUA GTC CTC TTC GGC AGA CTC TTG TGA-3' (situated within the last exon of HMGI-C and nested as compared to the one used in the first round) or UAP2 (5'-CUA CUA CUA CUA AAG GAT CCG TCG ACA TC-3'). CAU-tailing of the second round primers allowed the use of the directional CloneAmp cloning system (Life Technologies).


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Development of a 14q23–24 YAC and BAC Contig.
Using as starting points STS RM121 [corresponding to genomic t(12;14) breakpoint flanking sequences residing on chromosome 14; Ref. (12) ] and expressed sequence tag CH165 (corresponding to ectopic chromosome 14 sequences, which were isolated following a HMGI-C 3'-RACE experiment; Ref. 13 ), we constructed a YAC and BAC contig consisting of over 100 overlapping YACs and BACs as well as a corresponding rare-cutter physical map spanning ~2.7 Mb.4

FISH Definition of ULCR14.
Using well-characterized contig elements (mainly BACs or STS-specific genomic lambda clones) from this 2.7-Mb contig in FISH experiments, we were able to define a uterine leiomyoma breakpoint cluster region on chromosome 14q23–24 (ULCR14), in which all of the chromosome 14q23–24 breakpoints under investigation appeared to cluster. This cluster region, which by FISH analysis (seven cases) was defined as the region mapping between STS CH308 (contained within BAC 8A21) and ETS CH457 (contained within BAC 547J11), comprised a genomic interval of ~900 kb (Fig. 1)Citation . FISH analysis on normal metaphase spreads confirmed the reported mapping of ULCR14 at the border between 14q23 and 14q24 (results not shown). Subsequent integration (i.e., mapping) of published, well-characterized landmarks situated ULCR14 at ~62–64 cM relative to the most proximal (14pter) polymorphic marker, at a radiation hybrid position of 249–250 cR, at 0.7–1.6 Mb distal to AFMA116XD5 (Fig. 1)Citation .



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  		Fig. 1. Genomic organization of the RAD51B gene on chromosome 14 and expression- profiling of novel splice variants. Right, genetic, radiation, and physical (relative to marker AFMA116XD5) maps encompassing the chromosome 14 breakpoint region of uterine leiomyomas (ULCR14), including the relative mapping positions and transcriptional orientations of the RAD51B gene as well as two other known genes, i.e., ACTN1, encoding a cytoskeleton isoform of {alpha}-actinin, and EIF2A, encoding eukaryotic translation initiation factor 2{alpha}. The relative positions of anonymous expressed sequence tags (black bars) and STSs are also given. The exon/intron distribution of RAD51B is also given schematically, with indication of the encoded amino acid residues next to the corresponding exons. The alternatively spliced terminal coding exons are exons 11a–11c, and they contain different coding sequences. Left, Northern blot analysis revealed low-level (blot exposure was 14 days) expression of three related transcripts in specimens from uterus (with and without endometrium) but none in a variety of human fetal and adult tissue specimens and cell lines. These transcripts were shown in further studies to represent alternative splice variants of RAD51B. It should be noted, furthermore, that, thus far, Northern blot level expression of exon 11c has been detected only in primary uterine tissue, indicative for its tissue-restricted expression. Only a portion of the Northern blot results is shown. Included in these studies were, furthermore: (a) human adult tissue, including brain, colon (mucosal lining), kidney, liver, lung, pancreas, peripheral blood leukocytes, placenta, stomach, spleen, and thymus; (b) human fetal tissue, including brain, kidney, liver, and lung; and (c) cell lines, including A549 (lung carcinoma), G361 (melanoma), HeLa, HL60 (promyelocytic leukemia), K562 (CML), MOLT-4 (lymphoblastic leukemia), Raji (Burkitt’s lymphoma), and SW480 (colorectal adenocarcinoma). All Northern blots were purchased from Clontech Laboratories, Inc. Molecular weight markers are indicated.

 
Isolation and Characterization of Transcribed Sequences within ULCR14.
Using a variety of gene identification techniques (including random sequence sampling and 3' exon trapping), we identified several independent expressed sequences mapping within our 2.7-Mb contig. Among transcribed sequences residing within ULCR14 (Fig. 1Citation , right), those detected by Northern blot analysis with probe CH457 were particularly intriguing because they appeared to be part of transcripts of ~4.4 (major band), 7.0, and 1.6 (minor bands) kb expressed at low levels in uterus but not in any of the many other tissues and cell lines tested (Fig. 1Citation , left). Evaluation of corresponding cDNAs, isolated from cDNA libraries of human uterus and fetal brain, revealed CH457 sequences inframe fused to sequences of the RAD51B gene (8) . This observation was subsequently confirmed by RT-PCR. RAD51B expression (1.8-kb mRNA isoforms) is ubiquitous; more abundant, consistent with its proposed role in DNA repair; radiation inducible; and most prominent in tissues active in recombination (8, 9, 10) . Our results, therefore, clearly indicate the existence of as yet unknown, uterine splice variants of RAD51B. Interestingly, characterization of independent cDNA clones also indicated the presence of alternative polyadenylation signals within exon 11c because clones polyadenylating at different positions were isolated. Taking also into consideration the fact that splicing within the 3' untranslated region of genes is a very rare event, the use of alternative polyadenylation signals (possibly combined with exon skipping) is, therefore, very likely to be responsible for the various transcript sizes detected in Northern blots.

Structural Characterization of RAD51B.
The established exon/intron distribution revealed that RAD51B is composed of 13 exons, the last three of which serve as alternative last exons (Table 1)Citation . Subsequent physical mapping of these exons revealed that RAD51B has a genomic size of ~900 kb, almost completely encompassing ULCR14 (Fig. 1)Citation , with all characterized breakpoints mapping upstream of exon 11c (Fig. 2ACitation , arrows). Furthermore, Internet-mediated (protein) motif searching (at http://coot.embl-heidelberg.de/SMART/) revealed that RAD51B splice variants containing the unique stretch of 80 amino acids encoded by exon 11c contain a putative COOH-terminal transmembrane segment not present in the two previously published splice variants of RAD51B.


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  		Table 1 Genomic organization of the human RAD51B gene

 


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  		Fig. 2. Expression of hybrid transcripts in uterine leiomyoma, resulting from t(12;14)(q15;q23–24)-induced fusions between RAD51B and HMGIC. RT-PCR and 3'-RACE analyses were performed on cytogenetically well-characterized uterine leiomyomas. As an illustration, only the results of five representative and fully characterized cases (LM-30.1, LM-65, LM-100, LM-608, and LM-196.4) are presented. Primer sets used were designed on the basis of newly identified as well as known RAD51B (7 8 9) and HMGIC (4) sequences. Experimental conditions were as described previously (4) . A, wild-type mRNAs (with numbered exons) and deduced proteins of the developmentally regulated HMGIC gene (in blue) and the alternatively spliced RAD51B (in red) are depicted. The two highly conserved nucleotide binding Walker domains in RAD51B are marked (triangles) and the number of amino acids encoded by the three alternative terminal coding exons are indicated. Arrows indicate corresponding chromosome 12 and 14 breakpoints. B, HMGIC/RAD51B hybrid transcript (with numbered exons) and corresponding deduced fusion protein, as detected in cells of some of the uterine leiomyomas, as indicated. The three DNA binding domains encoded by exons 1–3 of HMGIC are marked. C, RAD51B/HMGIC hybrid transcripts and deduced fusion proteins, as detected in cells of the indicated uterine leiomyomas. Amino acid stretches encoded by frameshifted HMGIC sequences are depicted in green. Note that, in cases similar to LM-30.1, in which the chromosome 12 breakpoints occur upstream of exon 1 of HMGIC, no reciprocal HMGIC/RAD51B transcripts can be formed. Furthermore, the fact that HMGIC exon 1 is devoid of a 3' splice site results in the removal of this exon during the processing of a primary RAD51B/HMGIC fusion transcript, as is depicted in C.

 
3' RACE Analysis and RT-PCR.
Using 3'-RACE and RT-PCR analysis, we evaluated the existence of t(12;14) translocation-induced hybrid transcripts in six independent uterine leiomyoma specimens, all originating from different patients. 17 Independent clones containing fused sequences were fully characterized. Our results (schematically represented in Fig. 2Citation ) revealed that the predicted reading frames of the RAD51B/HMGIC transcripts code for variant truncations of the RAD51B protein, all lacking the 3' terminal exon (i.e., exon 11c, which encodes the 80-amino acid domain) and containing variable COOH-terminal ends, in some cases encoded by frameshifted HMGIC sequences. An important subgroup of RAD51B/HMGIC hybrids is expected to resemble the fusion transcript in LM-30.1 because the chromosome 12 breakpoints have been reported to frequently map upstream of HMGIC (14) , thereby excluding the existence of reciprocal (i.e., HMGIC/RAD51B) transcripts and, consequently, excluding these from a pathogenetically critical role. Furthermore, also in specimens in which breakpoints occurred within HMGIC, such reciprocal fusion transcripts were detected only in a few cases (Fig. 2)Citation .

Expression in the tumors of wild-type RAD51B and HMGIC transcripts was demonstrated by RT-PCR. Interestingly, RAD51B splice variants containing exon 11c were only detected in primary tumor samples investigated but not in any of the SV40 early region-transformed leiomyoma-derived cell lines tested thus far, thereby confirming the observed stringent tissue-specific splicing of this particular exon.

Conclusions.
On the basis of the data generated during the 3'-RACE and RT-PCR experiments, we propose that allelic knockout of particular uterine splice variants of RAD51B, resulting in expression of truncated and COOH-terminally altered RAD51B proteins, and dysregulation of HMGIC are tumor-specific features of uterine leiomyomas with t(12;14)(q15;q23–24) translocations. Pathogenetically, the observed dysregulations of RAD51B and HMGIC most likely act in conjunction, the former most probably conveying a tissue-dependent and the latter a more common effect. Furthermore, the link of RAD51B to tumorigenesis suggests that this gene may play a role in addition to its presumed recombination repair function. In line with such a pleiotropic, possibly splicing-dependent, role of RAD51B are observations with highly related family member RAD51A, which has been shown to promote ATP-dependent homologous pairing and strand transfer reactions in vitro (15) , play an essential role in mammalian cell viability (16 , 17) , and be linked etiologically to cancers, because of its interaction with p53 (18) , BCRA1 (19) , and BCRA2 (20) . Our data offer new viewpoints and unique tools for dissecting the tumorigenic processes in uterine leiomyoma and for deciphering functions of the intriguing recombination repair gene family.


   ACKNOWLEDGMENTS
 
We are grateful to Reinhilde Thoelen and Marleen Willems for their excellent technical assistance and to Janneke Schoenmakers for inspiring discussions and artwork. We apologize to all whose work we did not cite due to space constraints.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by the "Fonds voor Wetenschappelijk Onderzoek Vlaanderen," the "Geconcerteerde Onderzoekacties 1997–2001," and the "ASLK Programma voor Kankeronderzoek.". Back

2 To whom requests for reprints should be addressed, at the Laboratory for Molecular Oncology, Center for Human Genetics, University of Leuven, and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, B-3000 Leuven, Belgium. Phone: (32) 16-346076; Fax: (32) 16-346073; E-mail: Eric.Schoenmakers{at}med.kuleuven.ac.be Back

3 The abbreviations used are: YAC, yeast artificial chromosome; RACE, rapid amplification of cDNA ends; RT-PCR, reverse transcription-PCR; BAC, bacterial artificial chromosome; STS, sequence-tagged site; FISH, fluorescence in situ hybridization. Back

4 Unpublished data. Back

Received 10/ 7/98. Accepted 11/19/98.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

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E. Roijer, A. Nordkvist, A.-K. Strom, W. Ryd, M. Behrendt, J. Bullerdiek, J. Mark, and G. Stenman
Translocation, Deletion/Amplification, and Expression of HMGIC and MDM2 in a Carcinoma ex Pleomorphic Adenoma
Am. J. Pathol., February 1, 2002; 160(2): 433 - 440.
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 Proc. Natl. Acad. Sci. USAHome page
J.-Y. Masson, A. Z. Stasiak, A. Stasiak, F. E. Benson, and S. C. West
Complex formation by the human RAD51C and XRCC3 recombination repair proteins
PNAS, July 17, 2001; 98(15): 8440 - 8446.
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 Mol. Cell. Biol.Home page
M. Takata, M. S. Sasaki, S. Tachiiri, T. Fukushima, E. Sonoda, D. Schild, L. H. Thompson, and S. Takeda
Chromosome Instability and Defective Recombinational Repair in Knockout Mutants of the Five Rad51 Paralogs
Mol. Cell. Biol., April 15, 2001; 21(8): 2858 - 2866.
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 EndocrinologyHome page
H. Sumitani, M. Shozu, T. Segawa, K. Murakami, H.-J. Yang, K. Shimada, and M. Inoue
In Situ Estrogen Synthesized by Aromatase P450 in Uterine Leiomyoma Cells Promotes Cell Growth Probably Via an Autocrine/Intracrine Mechanism
Endocrinology, October 1, 2000; 141(10): 3852 - 3861.
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M. Takata, M. S. Sasaki, E. Sonoda, T. Fukushima, C. Morrison, J. S. Albala, S. M. A. Swagemakers, R. Kanaar, L. H. Thompson, and S. Takeda
The Rad51 Paralog Rad51B Promotes Homologous Recombinational Repair
Mol. Cell. Biol., September 1, 2000; 20(17): 6476 - 6482.
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K. Tanaka, T. Hiramoto, T. Fukuda, and K. Miyagawa
A Novel Human Rad54 Homologue, Rad54B, Associates with Rad51
J. Biol. Chem., August 18, 2000; 275(34): 26316 - 26321.
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