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1.
The t(14;18) translocation in follicular lymphoma is one of the most common chromosomal translocations. Breaks in chromosome 18 are localized at the 3'-UTR of BCL2 gene or downstream and are mainly clustered in either the major breakpoint region or the minor breakpoint cluster region (mcr). The recombination activating gene (RAG) complex induces breaks at IgH locus of chromosome 14, whereas the mechanism of fragility at BCL2 mcr remains unclear. Here, for the first time, we show that RAGs can nick mcr; however, the mechanism is unique. Three independent nicks of equal efficiency are generated, when both Mg(2+) and Mn(2+) are present, unlike a single nick during V(D)J recombination. Further, we demonstrate that RAG binding and nicking at the mcr are independent of nonamer, whereas a CCACCTCT motif plays a critical role in its fragility, as shown by sequential mutagenesis. More importantly, we recapitulate the BCL2 mcr translocation and find that mcr can undergo synapsis with a standard recombination signal sequence within the cells, in a RAG-dependent manner. Further, mutation to the CCACCTCT motif abolishes recombination within the cells, indicating its vital role. Hence, our data suggest a novel, physiologically relevant, nonamer-independent mechanism of RAG nicking at mcr, which may be important for generation of chromosomal translocations in humans. 相似文献
2.
Raghavan SC Chastain P Lee JS Hegde BG Houston S Langen R Hsieh CL Haworth IS Lieber MR 《The Journal of biological chemistry》2005,280(24):22749-22760
The most common chromosomal translocation in cancer, t(14;18), occurs at the bcl-2 major breakpoint region (Mbr) in follicular lymphomas. The 150-bp bcl-2 Mbr, which contains three breakage hotspots (peaks), has a single-stranded character and, hence, a non-B DNA conformation both in vivo and in vitro. Here, we use gel assays and electron microscopy to show that a triplex-specific antibody binds to the bcl-2 Mbr in vitro. Bisulfite reactivity shows that the non-B DNA structure is favored by, but not dependent upon, supercoiling and suggests a possible triplex conformation at one portion of the Mbr (peak I). We have used circular dichroism to test whether the predicted third strand of that suggested structure can indeed form a triplex with the duplex at peak I, and it does so with 1:1 stoichiometry. Using an intracellular minichromosomal assay, we show that the non-B DNA structure formation is critical for the breakage at the bcl-2 Mbr, because a 3-bp mutation that disrupts the putative peak I triplex also markedly reduces the recombination of the Mbr. A three-dimensional model of such a triplex is consistent with bond length, bond angle, and energetic restrictions (stacking and hydrogen bonding). We infer that an imperfect purine/purine/pyrimidine (R.R.Y) triplex likely forms at the bcl-2 Mbr in vitro, and in vivo recombination data favor this as the major DNA conformation in vivo as well. 相似文献
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Nan Yang Feiran Gong Luan Sun Dapeng Yang Xiao Han Changyan Ma Yujie Sun 《Journal of cellular biochemistry》2010,110(5):1208-1218
BCL2, originally identified as a proto‐oncogene in B‐cell lymphoma, is a key regulator of apoptosis. Although it is more than 200 kb in length, at least 70% of the t(14;18) translocation in follicular lymphomas occurs at the BCL2 major breakpoint region (mbr), located in the 3′‐untranslated region (3'‐UTR). We have previously found that the mbr is a regulatory element which positively regulates BCL2 expression and this regulatory function was closely associated with SATB1, which binds to a 37 bp mbr (37 mbr) in the 3′‐end of the mbr directly. However, the precise molecular mechanisms by which the mbr regulates gene expression are not fully understood. In this study, we purified Poly(ADP‐ribose) polymerase‐1 (PARP‐1) from the DNA–protein complexes formed by 37 mbr in Jurkat cells and demonstrated that PARP‐1 participates in the 37 mbr–protein complex's formation in vitro and in vivo. Functional analysis showed that overexpression of PARP‐1 decreases 37 mbr regulatory function and BCL2 expression. Conversely, knockdown of PARP‐1 with RNAi increases BCL2 expression. Taken together, the present findings indicate that PARP‐1 is a component of BCL2 37 mbr–protein complexes, and PARP‐1 is involved in the regulation of BCL2 expression. These findings are helpful in understanding the regulatory mechanisms of BCL2 expression. J. Cell. Biochem. 110: 1208–1218, 2010. Published 2010 Wiley‐Liss, Inc. 相似文献
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In follicular lymphoma the frequency of translocation t(14;18) varies considerably across different geographic regions ranging
from up to 89% among the American follicular lymphoma to around 30% in the Japanese lymphoma. Neighboring and regional countries
varied in their frequency reporting like in Israel (22 of 36 cases; 61%), Turkey (46 of 67 cases; 68.7%), and Jordan (4 of
5 cases; 80%). To our knowledge, this is the first study conducted in Lebanon to determine the frequency of this translocation
in follicular lymphoma patients. Of 42 cases diagnosed with follicular lymphoma at the American University of Beirut Medical
Center, amplifiable DNA was extracted from the corresponding paraffin embedded tissues and tested for t(14; 18) translocation
using PCR amplification of the MBR and MCR breakpoints (INVIVOSCRIBE, CA, USA). We found that 19 patients were positive for
t(14; 18) (45.2%) while 23 were negative (54.8%). Among the 19 positive cases, bcl2 was positive in 10 cases (52.6%). The
majority of the cases were positive for MBR (40.47%), while only two cases were positive for MCR (4.76%). This study expands
the geographical map of the distribution of bcl-2 gene rearrangement in follicular lymphoma patients in the Middle East region.
The interesting low frequency of t(14;18) in Lebanese follicular lymphoma patients (45.2%) stands out among several other
increased frequencies in surrounding and regional countries. In addition, in this patient population, there is a decreased
frequency of the MBR breakpoint (40.47%) while that reported in the literature ranges from 50 to 60%. 相似文献
7.
I Sidaner A Nivelon-Chevallier F Mugneret C Turc-Carel 《Journal de génétique humaine》1988,36(1-2):89-92
We report a de novo double reciprocal translocation, involving three chromosomes in a 25 year-old female patient, who has had twelve miscarriages. 相似文献
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A. A. Kennaugh S. V. Butterworth R. Hollis R. Baer T. H. Rabbitts A. M. R. Taylor 《Human genetics》1986,73(3):254-259
Summary The T cell receptor chain gene locus and the immunoglobulin heavy chain gene locus (IgH) have previously been mapped to the q11 and q32 positions respectively of the human chromosome 14. Both of these sites are also common breakpoints in lymphocytes from ataxia telangiectasia (A-T) patients. Using in situ hybridisation we show that the 14q32 breakpoint in an A-t non-leukaemic T cell clone with t(14;14) translocation, lies outside the IgH locus and proximal to it with respect to the centromere. The 14q11-14qter segment of the homologous chromosome 14 carrying the constant gene region of the chain locus is translocated to this 14q32 position. 相似文献
9.
Heckman CA Mehew JW Ying GG Introna M Golay J Boxer LM 《The Journal of biological chemistry》2000,275(9):6499-6508
In follicular lymphoma, bcl-2 is translocated to the immunoglobulin heavy chain locus leading to deregulation of bcl-2 expression. We examined the role of Myb proteins in the regulation of bcl-2 expression in lymphoma cells. We showed that A-Myb up-regulates bcl-2 promoter activity. Northern and Western analyses demonstrated that A-Myb was expressed in the DHL-4 t(14;18) cell line. In t(14;18) cells and mature B cells, A-Myb up-regulated bcl-2 expression, whereas B- and c-Myb had little effect on bcl-2 gene expression. Deletion analysis of the bcl-2 5'-region identified a region responsive to A-Myb in t(14;18) cells. A potential binding site for the Cdx homeodomain proteins was located in this sequence. Analysis of the A-Myb-responsive region by UV cross-linking experiments revealed that a 32-kDa protein formed a complex with this region, but direct binding by Myb proteins could not be demonstrated. A-Myb could be recovered along with Cdx2 when nuclear extracts were passed over the Cdx site. Mutagenesis of the Cdx binding site abolished binding by the 32-kDa protein and significantly reduced the ability of A-Myb to induce bcl-2 expression. A strong induction of bcl-2 P2 promoter activity was observed in cotransfection studies of DHL-4 cells with the A-Myb and Cdx2 expression vectors, and increased endogenous Bcl-2 protein expression was observed in B cells transfected with A-Myb and/or Cdx2 expression constructs. 相似文献
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David R. Abbott Robert T. Abbott Stephen D. Jenson G. Chris Fillmore Kojo S. J. Elenitoba-Johnson Megan S. Lim 《Journal of Hematopathology》2009,2(2):113-119
Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas. 相似文献
12.
O. Bartsch Georg K. Hinkel Michael B. Petersen Ulrich König Merete Bugge Margareta Mikkelsen Dimitris Avramopoulos Michael Morris Stylianos E. Antonarakis 《Human genetics》1997,100(5-6):669-675
We describe a 17-month-old infant with clinical features of Down syndrome and a normal karyotype by standard chromosomal analysis,
her two uncles aged 28 and 30 years, respectively, with reduced intelligence and unusual appearance but not apparent Down
syndrome, and a severely retarded 6-year-old girl with dysmorphy and epilepsy from the same family. Cytogenetic studies of
patients and normal intervening relatives had been carried out at different institutions with normal results. Fluorescence
in situ hybridization using whole chromosome painting and unique-copy probes (cosmids) and high-resolution banding revealed
a familial subtelomeric translocation of chromosomes 18 and 21, resulting in partial trisomy 21 in the infant and her two
uncles, and partial monosomy 21 in the 6-year-old girl. Cytogenetic breakpoints were located in bands 18q23 and 21q22.1, respectively.
The molecular breakpoint on chromosome 21 was located between D21S211 (proximal) and D21S1283 (distal) and thus maps within
the Down syndrome critical region.
Received: 11 November 1996 / Accepted: 29 April 1997 相似文献
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McCarthy BA Boyle E Wang XP Guzowski D Paul S Catera R Trott J Yan XJ Croce CM Damle R Yancopoulos S Messmer BT Lesser M Allen SL Rai KR Chiorazzi N 《Molecular medicine (Cambridge, Mass.)》2008,14(9-10):618-627
Since its discovery in follicular lymphoma cells at the breakpoint t(14;18), Bcl-2 has been studied extensively in many basic and clinical science settings. Bcl-2 can locate as an integral mitochondrial membrane component, where its primary role is to block apoptosis by maintaining membrane integrity. Here we show that Bcl-2 also can position on the outer cell surface membrane of B cells from patients with chronic lymphocytic leukemia (B-CLL) and certain other leukemias that do not classically possess the chromosomal breakpoint t(14;18). Although low levels of Bcl-2 can be detected on the surface membrane of apparently healthy leukemic and normal B cells, expression of Bcl-2 correlates best with spontaneous or induced apoptosis. Notably, upon induction of apoptosis, B-CLL cells were much more efficient in upregulating surface Bcl-2 than normal B cells. It is not clear if this surface membrane expression is a passive consequence of the apoptotic process or an active attempt by the B cell to abort cell death by stabilizing the plasma membrane. 相似文献
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Tourette syndrome in a pedigree with a 7;18 translocation: identification of a YAC spanning the translocation breakpoint at 18q22.3. 总被引:2,自引:1,他引:1
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L. Boghosian-Sell D. E. Comings J. Overhauser 《American journal of human genetics》1996,59(5):999-1005
Tourette syndrome is a neuropsychiatric disorder characterized by the presence of multiple, involuntary motor and vocal tics. Associated pathologies include attention deficit disorder and obsessive-compulsive disorder (OCD). Extensive linkage analysis based on an autosomal dominant mode of transmission with reduced penetrance has failed to show linkage with polymorphic markers, suggesting either locus heterogeneity or a polygenic origin for Tourette syndrome. An individual diagnosed with Tourette syndrome has been described carrying a constitutional (7;18) chromosome translocation (Comings et al. 1986). Other family members carrying the translocation exhibit features seen in Tourette syndrome including motor tics, vocal tics, and OCD. Since the disruption of specific genes by a chromosomal rearrangement can elicit a particular phenotype, we have undertaken the physical mapping of the 7;18 translocation such that genes mapping at the site of the breakpoint can be identified and evaluated for a possible involvement in Tourette syndrome. Using somatic cell hybrids retaining either the der(7) or the der(18), a more precise localization of the breakpoints on chromosomes 7 and 18 have been determined. Furthermore, physical mapping has identified two YAC clones that span the translocation breakpoint on chromosome 18 as determined by FISH. These YAC clones will be useful for the eventual identification of genes that map to chromosomes 7 and 18 at the site of the translocation. 相似文献
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Modulated binding of SATB1, a matrix attachment region protein, to the AT-rich sequence flanking the major breakpoint region of BCL2 总被引:4,自引:0,他引:4
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Ramakrishnan M Liu WM DiCroce PA Posner A Zheng J Kohwi-Shigematsu T Krontiris TG 《Molecular and cellular biology》2000,20(3):868-877
The t(14,18) chromosomal translocation that occurs in human follicular lymphoma constitutively activates the BCL2 gene and disrupts control of apoptosis. Interestingly, 70% of the t(14,18) translocations are confined to three 15-bp clusters positioned within a 150-bp region (major breakpoint region or [MBR]) in the untranslated portion of terminal exon 3. We analyzed DNA-protein interactions in the MBR, as these may play some role in targeting the translocation to this region. An 87-bp segment (87MBR) immediately 3' to breakpoint cluster 3 was essential for DNA-protein interaction monitored with mobility shift assays. We further delineated a core binding region within 87MBR: a 33-bp, very AT-rich sequence highly conserved between the human and mouse BCL2 gene (37MBR). We have purified and identified one of the core factors as the matrix attachment region (MAR) binding protein, SATB1, which is known to bind to AT-rich sequences with a high propensity to unwind. Additional factors in nuclear extracts, which we have not yet characterized further, increased SATB1 affinity for the 37MBR target four- to fivefold. Specific binding activity within 37MBR displayed cell cycle regulation in Jurkat T cells, while levels of SATB1 remained constant throughout the cell cycle. Finally, we demonstrated in vivo binding of SATB1 to the MBR, strongly suggesting the BCL2 major breakpoint region is a MAR. We discuss the potential consequences of our observations for both MBR fragility and regulatory function. 相似文献
20.
The t(8;14) breakpoint of the EW 36 undifferentiated lymphoma cell line lies 5' of MYC in a region prone to involvement in endemic Burkitt's lymphomas 总被引:2,自引:1,他引:1
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One of the best analyzed tumor-specific cytogenetic abnormalities is the t(8;14) chromosomal translocation observed in cases of Burkitt's and undifferentiated lymphomas (ULs), and acute lymphoblastic leukemias (ALLs). Here we analyze the cloned (8;14) chromosomal breakpoint of the UL cell line EW 36. We show that the region of chromosome 8 involved in the translocation is situated near a site previously demonstrated to harbor a cluster of endemic Burkitt's lymphoma breakpoints, approximately 50 kb 5' of MYC. In those cases, we demonstrated that malfunction of the V-D-J recombinase generated the translocations. However, in this case the isotype switch mechanism of translocation is implicated: at the breakpoint, S mu/S gamma and C gamma sequences are found on chromosome 14. Thus, the features of the EW 36 t(8;14) breakpoint are consonant with our model for B-cell lymphomagenesis which relates the precursor cell that gives rise to malignancy, the mechanism of translocation, and the phenotype of the tumor. 相似文献