- Open Access
Anchoring the genome
© BioMed Central Ltd 2008
Published: 22 January 2008
Although the principles governing chromosomal architecture are largely unresolved, there is evidence that higher-order chromatin folding is mediated by the anchoring of specific DNA sequences to the nuclear matrix. These genome anchors are also crucial regulators of gene expression and DNA replication, and play a role in pathogenesis.
The architecture of interphase chromosomes presents a major challenge for our understanding of the functioning of the mammalian genome. Chromosomes are composed of hierarchical levels of chromatin loops or folds. Several models have attempted to describe chromatin organization above the level of the nucleosomal fiber [1–3]. Of these, the 'multi-loop subcompartment' model, in which rosettes of approximately 1-2 Mb are built up from smaller chromatin loops of 50-200 kb, is compatible with most of the recent experimental findings . Although there is no definitive proof so far for this or any other model of higher-order chromatin architecture, it is clear that the folding and looping of chromatin leads to the formation of discrete 'territories' for individual chromosomes in the interphase nucleus . Accumulating experimental evidence suggests that these chromatin loops or folds are maintained by attachments to the nuclear matrix .
The nuclear matrix extends throughout the nucleus and consists of proteins that are retained after unbound chromatin and soluble proteins are removed using high-strength ionic buffers [6–9]. Although the nature of the nuclear matrix is still under debate , it has achieved prominence as many of its best-characterized components, including lamins, topoisomerase II, special AT-rich sequence binding protein 1 (SATB1) and scaffold attachment factor-B1 (SAFB1), are key players in fundamental nuclear processes [10–13]. In eukaryotic organisms, chromatin is anchored to the nuclear matrix by short DNA sequences of about 100-2,000 bp called matrix attachment regions (MARs) [5, 14]. The strong interaction between MARs and the insoluble proteins of the nuclear matrix protects these sequences from high-strength ionic buffers and nuclease digestion . In general, MARs are rich in AT and repetitive sequences, and map to regions where the DNA is intrinsically curved or kinked and has a propensity for base unpairing [15–19]. The spacing of AT sequences is crucial for matrix binding, but there is no consensus DNA motif for the estimated 30,000-80,000 MARs in the human genome [6, 20].
MARs are bound to the nuclear matrix either constitutively or transiently. The higher-order chromatin structure of interphase and metaphase chromosomes is likely to be maintained by constitutive MARs. The dynamic associations of transient MARs are more likely to be implicated in genomic function, as they correlate with transcription or replication of the genetic loci with which they are associated . In this review, we draw together evidence from higher eukaryotes that, further to their role in chromosome structure, MARs are key mediators of genome regulation, and we will discuss their roles in human disease.
MARs and transcriptional regulation
The tethering of DNA to the nuclear matrix plays a vital role in transcription [9, 21, 22]. Using T-cell differentiation as a model we will describe how MARs facilitate transcription and reveal how they shape chromatin architecture to insulate chromatin domains from the effects of flanking chromatin.
Upon stimulation by antigen, naive CD4 helper T cells differentiate into effector Th1 and Th2 cells. In mice, Ifng (the gene for the cytokine interferon-γ) is silenced in naive T cells but transcribed in activated Th1 cells. The architecture of the Ifng locus has been analyzed in these two cell types by a combination of chromosome conformation capture and microarray technology . In naive T cells Ifng was found to exist in a linear conformation, but in Th1 cells it is present in a chromatin loop, due to tethering of DNA to the nuclear matrix by MARs 7 kb upstream and 14 kb downstream of the locus. The absence of this selective DNA attachment to the nuclear matrix in naive T cells suggests that dynamic DNA anchors mediate the formation of the looped structure and the expression of the Ifng locus .
The molecular mechanisms by which MARs reorganize higher-order chromatin structure have been investigated in detail at the murine Th2 cytokine locus, which contains the cluster of coordinately regulated genes Il4, Il13 and Il5 in a region of about 120 kb . These genes are expressed in Th2 cells but are silent in naive T cells. Following Th2 activation, expression of the nuclear matrix protein SATB1 is rapidly induced, and MARs within the locus mediate the formation of small loops by anchoring the loops onto a common protein core associated with SATB1 . Down-regulation of SATB1 expression by RNA interference prevents both the formation of this looped structure and transcriptional activation of the locus . In SATB1-null thymocytes (developing T cells) the expression of many genes is spatially and temporally misregulated, and T-cell development in SATB1-deficient mice is prematurely blocked. These results indicate that the binding of SATB1 at MARs regulates the expression of T-cell differentiation genes by reorganizing higher-order chromatin architecture [24, 25]. A similar MAR-mediated loop-formation mechanism regulates expression of the human β-globin gene cluster [26, 27].
Many genes are known to be shielded by so-called 'insulator' elements from stimulatory or repressive effects attributable to the chromatin state and regulatory elements in flanking regions. MARs commonly map to sequences flanking genes, and co-localize with some of the most extensively analyzed insulator elements, including gypsy, a retrotransposon in Drosophila melanogaster, suggesting that MARs have an insulator function . In Drosophila, the nuclear matrix protein Su(Hw) binds to gypsy, creating chromatin loops . Certain mutations in Su(Hw) that disrupt the loop structures render the insulator non-functional [34, 35]. This suggests that the tethering of MARs to the nuclear matrix topologically constrains the DNA into looped structures, protecting the intervening DNA from the influence of cis-regulatory elements outside the loop. In vertebrates, CTCF, a ubiquitous nuclear matrix protein, binds to insulators and has also been shown to interact with MARs . While the precise mechanisms of CTCF insulation remain unclear, the binding of CTCF to MARs might block interactions between promoters and unrelated enhancers and create looped structures that delimit different chromosomal domains . Experiments in a wide variety of higher eukaryotes have shown that in stably transfected cells, MAR-containing transgenes were expressed at higher levels compared with transgenes lacking MARs, indicating that the MARs shield the transgenes from the effects of the neighboring host chromatin [38, 39].
Taken together, the experimental evidence described above supports the view that MARs function as landing platforms for a wide range of matrix proteins. Such interactions form complex higher-order nucleoprotein structures, which insulate chromatin domains and also control gene expression by forming bridges between components of the basal transcription machinery and distal and proximal regulatory elements. MARs can thus be defined as cis-acting elements constituting a critical layer of transcriptional regulation.
MARs and DNA replication
To ensure that the genome is copied accurately, and only once per cell cycle, eukaryotes have evolved intricate mechanisms to regulate DNA replication. Some of the best-characterized origins of replication (ORIs) have been mapped to AT-rich genomic regions with base-unpairing elements. Futhermore, sequences at or near the ORIs for the human lamin B2 gene, the Chinese hamster dihydrofolate reductase β and β' genes, the human β-globin gene, the chicken α-globin and lysozyme genes, and the Xenopus and mouse c-myc genes, function as dynamic MARs during the cell cycle [40–46].
These findings are in agreement with observations that DNA replication is temporally and spatially ordered in the nuclei of animal cells. Several replicons are coordinately replicated at foci in the S-phase nucleus [47, 48]. Evidence that replication foci are associated with the nuclear matrix came first from electron microscopy . Further support came from a study of nuclear matrix structures where DNA synthesis occurred at replication sites that were indistinguishable from those found in intact cells . Radichev and colleagues  found that DNA replication initiates at discrete chromosomal sites attached to the nuclear matrix.
At replication foci, the nuclear matrix houses factors necessary for DNA replication, such as DNA polymerases, the sliding clamp (PCNA) and single-strand binding protein (RPA), and provides structural support throughout the replication process. Wu and Gilbert  proposed that origins are selected and replicon size is determined in early G1 phase of the cell cycle. Using an in vitro system, it was subsequently shown that MCM2, a component of the pre-replicative complex, is loaded onto chromatin gradually and cumulatively throughout G1, but is rapidly excluded from active replication foci in S phase . Tatsumi and colleagues  reported a similar cycle of events for ORC1, a component of the replication initiation complex at ORIs. This coincides with recruitment of the chromatin-bound ORC2-5 complex to a structure likely to be the nuclear matrix , suggesting a link between the accumulation of ORC1 and the assembly of the replication complex in human nuclei.
Genome anchoring and disease
MARs also appear to play a role in some cancers. Chromosome rearrangements are hallmarks of certain malignancies and inherited genetic disorders. The breakpoints of recurrent translocations in leukemia as well as deletions involving the breast-cancer susceptibility genes BRCA1 and BRCA2 occur at MARs, indicating that the bringing together of these sequences at the nuclear matrix facilitates their illegitimate recombination [61, 62]. Patients who develop leukemia following treatment of a primary tumor with inhibitors of topoisomerase II often have specific chromosome translocations in their cancer cells whose breakpoints contain MARs, emphasizing the importance of the chromatin environment in the generation of chromosome aberrations [63, 64].
Fragile sites are hypervariable regions that generate genomic instability in tumors. Certain fragile sites contain long AT-rich minisatellites, called AT-islands, which function as MARs . AT-islands are susceptible to considerable repeat expansion, which, in the fragile site FRA16B associated with leukemia, appears to strengthen their attachment to the nuclear matrix . The presence of abnormal transcripts of the tumor suppressor gene WWOX (which spans FRA16B) in the absence of detectable mutations or deletions may be caused by aberrant chromatin architecture due to enhanced MAR anchoring by expanded AT-islands .
Our understanding of how the genome functions in the context of the nucleus has been propelled by indisputable evidence that distinct genomic sites bind to regulatory proteins at the nuclear matrix. The emerging picture is that these genomic anchors regulate transcription and replication by dynamically organizing chromatin in three-dimensional space. The recognition that these essential nuclear processes are compartmentalized into microenvironments that are compromised in diseases such as cancer  emphasizes the need to define chromatin architecture more accurately in relation to the various nuclear domains. In reaching beyond the linear genome, we will approach a more comprehensive view of genomic function and are likely to identify truly novel targets for therapy.
We thank Stephen A Krawetz, Amelia K Linnemann, and members of our laboratory for helpful comments and discussions. All authors contributed to the writing of the paper. DO was supported by the Cancer Research UK London Research Institute. EL, PT and DS were supported by Cancer Research UK Programme Grant C5321/A8318.
- Belmont AS, Bruce K: Visualization of G1 chromosomes: a folded, twisted, supercoiled chromonema model of interphase chromatid structure. J Cell Biol. 1994, 127: 287-302. 10.1083/jcb.127.2.287.PubMedView ArticleGoogle Scholar
- Sachs RK, van den Engh G, Trask B, Yokota H, Hearst JE: A random-walk/giant-loop model for interphase chromosomes. Proc Natl Acad Sci USA. 1995, 92: 2710-2714. 10.1073/pnas.92.7.2710.PubMedPubMed CentralView ArticleGoogle Scholar
- Munkel C, Eils R, Dietzel S, Zink D, Mehring C, Wedemann G, Cremer T, Langowski J: Compartmentalization of interphase chromosomes observed in simulation and experiment. J Mol Biol. 1999, 285: 1053-1065. 10.1006/jmbi.1998.2361.PubMedView ArticleGoogle Scholar
- Cremer T, Cremer C: Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present. Eur J Histochem. 2006, 50: 223-272.PubMedGoogle Scholar
- Berezney R, Mortillaro MJ, Ma H, Wei X, Samarabandu J: The nuclear matrix: a structural milieu for genomic function. Int Rev Cytol. 1995, 162A: 1-65.PubMedGoogle Scholar
- Bode J, Goetze S, Heng H, Krawetz SA, Benham C: From DNA structure to gene expression: mediators of nuclear compartmentalization and dynamics. Chromosome Res. 2003, 11: 435-445. 10.1023/A:1024918525818.PubMedView ArticleGoogle Scholar
- Jackson DA: The principles of nuclear structure. Chromosome Res. 2003, 11: 387-401. 10.1023/A:1024954123092.PubMedView ArticleGoogle Scholar
- Nickerson J: Experimental observations of a nuclear matrix. J Cell Sci. 2001, 114: 463-474.PubMedGoogle Scholar
- Heng HH, Goetze S, Ye CJ, Liu G, Stevens JB, Bremer SW, Wykes SM, Bode J, Krawetz SA: Chromatin loops are selectively anchored using scaffold/matrix-attachment regions. J Cell Sci. 2004, 117: 999-1008. 10.1242/jcs.00976.PubMedView ArticleGoogle Scholar
- Adachi Y, Kas E, Laemmli UK: Preferential, cooperative binding of DNA topoisomerase II to scaffold-associated regions. EMBO J. 1989, 8: 3997-4006.PubMedPubMed CentralGoogle Scholar
- Luderus ME, den Blaauwen JL, de Smit OJ, Compton DA, van Driel R: Binding of matrix attachment regions to lamin polymers involves single-stranded regions and the minor groove. Mol Cell Biol. 1994, 14: 6297-6305.PubMedPubMed CentralView ArticleGoogle Scholar
- Cai S, Lee CC, Kohwi-Shigematsu T: SATB1 packages densely looped, transcriptionally active chromatin for coordinated expression of cytokine genes. Nat Genet. 2006, 38: 1278-1288. 10.1038/ng1913.PubMedView ArticleGoogle Scholar
- Townson SM, Kang K, Lee AV, Oesterreich S: Structure-function analysis of the estrogen receptor alpha corepressor scaffold attachment factor-B1: identification of a potent transcriptional repression domain. J Biol Chem. 2004, 279: 26074-26081. 10.1074/jbc.M313726200.PubMedView ArticleGoogle Scholar
- Singh GB, Kramer JA, Krawetz SA: Mathematical model to predict regions of chromatin attachment to the nuclear matrix. Nucleic Acids Res. 1997, 25: 1419-1425. 10.1093/nar/25.7.1419.PubMedPubMed CentralView ArticleGoogle Scholar
- Kohwi-Shigematsu T, Kohwi Y: Torsional stress stabilizes extended base unpairing in suppressor sites flanking immunoglobulin heavy chain enhancer. Biochemistry. 1990, 29: 9551-9560. 10.1021/bi00493a009.PubMedView ArticleGoogle Scholar
- von Kries JP, Phi-Van L, Diekmann S, Stratling WH: A non-curved chicken lysozyme 5' matrix attachment site is 3' followed by a strongly curved DNA sequence. Nucleic Acids Res. 1990, 18: 3881-3885. 10.1093/nar/18.13.3881.PubMedPubMed CentralView ArticleGoogle Scholar
- Bode J, Kohwi Y, Dickinson L, Joh T, Klehr D, Mielke C, Kohwi-Shigematsu T: Biological significance of unwinding capability of nuclear matrix-associating DNAs. Science. 1992, 255: 195-197. 10.1126/science.1553545.PubMedView ArticleGoogle Scholar
- Fiorini A, Gouveia Fde S, Fernandez MA: Scaffold/matrix attachment regions and intrinsic DNA curvature. Biochemistry (Mosc). 2006, 71: 481-488. 10.1134/S0006297906050038.View ArticleGoogle Scholar
- Liebich I, Bode J, Reuter I, Wingender E: Evaluation of sequence motifs found in scaffold/matrix-attached regions (S/MARs). Nucleic Acids Res. 2002, 30: 3433-3442. 10.1093/nar/gkf446.PubMedPubMed CentralView ArticleGoogle Scholar
- Linnemann AK, Platts AE, Doggett N, Gluch A, Bode J, Krawetz SA: Genomewide identification of nuclear matrix attachment regions: an analysis of methods. Biochem Soc Trans. 2007, 35: 612-617. 10.1042/BST0350612.PubMedView ArticleGoogle Scholar
- Geyer PK: The role of insulator elements in defining domains of gene expression. Curr Opin Genet Dev. 1997, 7: 242-248. 10.1016/S0959-437X(97)80134-7.PubMedView ArticleGoogle Scholar
- Eivazova ER, Vassetzky YS, Aune TM: Selective matrix attachment regions in T helper cell subsets support loop conformation in the Ifng gene. Genes Immun. 2007, 8: 35-43. 10.1038/sj.gene.6364349.PubMedView ArticleGoogle Scholar
- Loots GG, Locksley RM, Blankespoor CM, Wang ZE, Miller W, Rubin EM, Frazer KA: Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science. 2000, 288: 136-140. 10.1126/science.288.5463.136.PubMedView ArticleGoogle Scholar
- Alvarez JD, Yasui DH, Niida H, Joh T, Loh DY, Kohwi-Shigematsu T: The MAR-binding protein SATB1 orchestrates temporal and spatial expression of multiple genes during T-cell development. Genes Dev. 2000, 14: 521-535.PubMedPubMed CentralGoogle Scholar
- Cai S, Han HJ, Kohwi-Shigematsu T: Tissue-specific nuclear architecture and gene expression regulated by SATB1. Nat Genet. 2003, 34: 42-51. 10.1038/ng1146.PubMedView ArticleGoogle Scholar
- Ostermeier GC, Liu Z, Martins RP, Bharadwaj RR, Ellis J, Draghici S, Krawetz SA: Nuclear matrix association of the human beta-globin locus utilizing a novel approach to quantitative real-time PCR. Nucleic Acids Res. 2003, 31: 3257-3266. 10.1093/nar/gkg424.PubMedPubMed CentralView ArticleGoogle Scholar
- Wen J, Huang S, Rogers H, Dickinson LA, Kohwi-Shigematsu T, Noguchi CT: SATB1 family protein expressed during early erythroid differentiation modifies globin gene expression. Blood. 2005, 105: 3330-3339. 10.1182/blood-2004-08-2988.PubMedView ArticleGoogle Scholar
- Donev R, Horton R, Beck S, Doneva T, Vatcheva R, Bowen WR, Sheer D: Recruitment of heterogeneous nuclear ribonucleoprotein A1 in vivo to the LMP/TAP region of the major histocompatibility complex. J Biol Chem. 2003, 278: 5214-5226. 10.1074/jbc.M206621200.PubMedView ArticleGoogle Scholar
- Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF: Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol. 2006, 26: 4758-4768. 10.1128/MCB.02009-05.PubMedPubMed CentralView ArticleGoogle Scholar
- Szentirmay MN, Sawadogo M: Spatial organization of RNA polymerase II transcription in the nucleus. Nucleic Acids Res. 2000, 28: 2019-2025. 10.1093/nar/28.10.2019.PubMedPubMed CentralView ArticleGoogle Scholar
- Hart CM, Laemmli UK: Facilitation of chromatin dynamics by SARs. Curr Opin Genet Dev. 1998, 8: 519-525. 10.1016/S0959-437X(98)80005-1.PubMedView ArticleGoogle Scholar
- Kimura H, Tao Y, Roeder RG, Cook PR: Quantitation of RNA polymerase II and its transcription factors in an HeLa cell: little soluble holoenzyme but significant amounts of polymerases attached to the nuclear substructure. Mol Cell Biol. 1999, 19: 5383-5392.PubMedPubMed CentralView ArticleGoogle Scholar
- Nabirochkin S, Ossokina M, Heidmann T: A nuclear matrix/scaffold attachment region co-localizes with the gypsy retrotransposon insulator sequence. J Biol Chem. 1998, 273: 2473-2479. 10.1074/jbc.273.4.2473.PubMedView ArticleGoogle Scholar
- Byrd K, Corces VG: Visualization of chromatin domains created by the gypsy insulator of Drosophila. J Cell Biol. 2003, 162: 565-574. 10.1083/jcb.200305013.PubMedPubMed CentralView ArticleGoogle Scholar
- Valenzuela L, Kamakaka RT: Chromatin insulators. Annu Rev Genet. 2006, 40: 107-138. 10.1146/annurev.genet.39.073003.113546.PubMedView ArticleGoogle Scholar
- Yusufzai TM, Felsenfeld G: The 5'-HS4 chicken beta-globin insulator is a CTCF dependent nuclear matrix-associated element. Proc Natl Acad Sci USA. 2004, 101: 8620-8624. 10.1073/pnas.0402938101.PubMedPubMed CentralView ArticleGoogle Scholar
- Dunn KL, Zhao H, Davie JR: The insulator binding protein CTCF associates with the nuclear matrix. Exp Cell Res. 2003, 288: 218-223. 10.1016/S0014-4827(03)00185-X.PubMedView ArticleGoogle Scholar
- Halweg C, Thompson WF, Spiker S: The rb7 matrix attachment region increases the likelihood and magnitude of transgene expression in tobacco cells: a flow cytometric study. Plant Cell. 2005, 17: 418-429. 10.1105/tpc.104.028100.PubMedPubMed CentralView ArticleGoogle Scholar
- Girod PA, Nguyen DQ, Calabrese D, Puttini S, Grandjean M, Martinet D, Regamey A, Saugy D, Beckmann JS, Bucher P, Mermod N: Genome-wide prediction of matrix attachment regions that increase gene expression in mammalian cells. Nat Methods. 2007, 4: 747-753. 10.1038/nmeth1076.PubMedView ArticleGoogle Scholar
- Razin SV, Vassetzky YS, Hancock R: Nuclear matrix attachment regions and topoisomerase II binding and reaction sites in the vicinity of a chicken DNA replication origin. Biochem Biophys Res Commun. 1991, 177: 265-270. 10.1016/0006-291X(91)91977-K.PubMedView ArticleGoogle Scholar
- Lagarkova MA, Svetlova E, Giacca M, Falaschi A, Razin SV: DNA loop anchorage region colocalizes with the replication origin located downstream to the human gene encoding lamin B2. J Cell Biochem. 1998, 69: 13-18. 10.1002/(SICI)1097-4644(19980401)69:1<13::AID-JCB2>3.0.CO;2-Y.PubMedView ArticleGoogle Scholar
- Phi-van L, Sellke C, von Bodenhausen A, Stratling WH: An initiation zone of chromosomal DNA replication at the chicken lysozyme gene locus. J Biol Chem. 1998, 273: 18300-18307. 10.1074/jbc.273.29.18300.PubMedView ArticleGoogle Scholar
- Djeliova V, Russev G, Anachkova B: Dynamics of association of origins of DNA replication with the nuclear matrix during the cell cycle. Nucleic Acids Res. 2001, 29: 3181-3187. 10.1093/nar/29.15.3181.PubMedPubMed CentralView ArticleGoogle Scholar
- Djeliova V, Russev G, Anachkova B: Distribution of DNA replication origins between matrix-attached and loop DNA in mammalian cells. J Cell Biochem. 2001, 80: 353-359. 10.1002/1097-4644(20010301)80:3<353::AID-JCB80>3.0.CO;2-Y.PubMedView ArticleGoogle Scholar
- Mesner LD, Hamlin JL, Dijkwel PA: The matrix attachment region in the Chinese hamster dihydrofolate reductase origin of replication may be required for local chromatid separation. Proc Natl Acad Sci USA. 2003, 100: 3281-3286. 10.1073/pnas.0437791100.PubMedPubMed CentralView ArticleGoogle Scholar
- Girard-Reydet C, Gregoire D, Vassetzky Y, Mechali M: DNA replication initiates at domains overlapping with nuclear matrix attachment regions in the Xenopus and mouse c-myc promoter. Gene. 2004, 332: 129-138. 10.1016/j.gene.2004.02.031.PubMedView ArticleGoogle Scholar
- Jackson DA, Pombo A: Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J Cell Biol. 1998, 140: 1285-1295. 10.1083/jcb.140.6.1285.PubMedPubMed CentralView ArticleGoogle Scholar
- Ma H, Samarabandu J, Devdhar RS, Acharya R, Cheng PC, Meng C, Berezney R: Spatial and temporal dynamics of DNA replication sites in mammalian cells. J Cell Biol. 1998, 143: 1415-1425. 10.1083/jcb.143.6.1415.PubMedPubMed CentralView ArticleGoogle Scholar
- Hozak P, Hassan AB, Jackson DA, Cook PR: Visualization of replication factories attached to nucleoskeleton. Cell. 1993, 73: 361-373. 10.1016/0092-8674(93)90235-I.PubMedView ArticleGoogle Scholar
- Nakayasu H, Berezney R: Mapping replicational sites in the eucaryotic cell nucleus. J Cell Biol. 1989, 108: 1-11. 10.1083/jcb.108.1.1.PubMedView ArticleGoogle Scholar
- Radichev I, Parashkevova A, Anachkova B: Initiation of DNA replication at a nuclear matrix-attached chromatin fraction. J Cell Physiol. 2005, 203: 71-77. 10.1002/jcp.20203.PubMedView ArticleGoogle Scholar
- Wu JR, Gilbert DM: A distinct G1 step required to specify the Chinese hamster DHFR replication origin. Science. 1996, 271: 1270-1272. 10.1126/science.271.5253.1270.PubMedView ArticleGoogle Scholar
- Dimitrova DS, Todorov IT, Melendy T, Gilbert DM: Mcm2, but not RPA, is a component of the mammalian early G1-phase prereplication complex. J Cell Biol. 1999, 146: 709-722. 10.1083/jcb.146.4.709.PubMedPubMed CentralView ArticleGoogle Scholar
- Tatsumi Y, Ohta S, Kimura H, Tsurimoto T, Obuse C: The ORC1 cycle in human cells: I. cell cycle-regulated oscillation of human ORC1. J Biol Chem. 2003, 278: 41528-41534. 10.1074/jbc.M307534200.PubMedView ArticleGoogle Scholar
- Ohta S, Tatsumi Y, Fujita M, Tsurimoto T, Obuse C: The ORC1 cycle in human cells: II. Dynamic changes in the human ORC complex during the cell cycle. J Biol Chem. 2003, 278: 41535-41540. 10.1074/jbc.M307535200.PubMedView ArticleGoogle Scholar
- Shera KA, Shera CA, McDougall JK: Small tumor virus genomes are integrated near nuclear matrix attachment regions in transformed cells. J Virol. 2001, 75: 12339-12346. 10.1128/JVI.75.24.12339-12346.2001.PubMedPubMed CentralView ArticleGoogle Scholar
- Rampalli S, Kulkarni A, Kumar P, Mogare D, Galande S, Mitra D, Chattopadhyay S: Stimulation of Tat-independent transcriptional processivity from the HIV-1 LTR promoter by matrix attachment regions. Nucleic Acids Res. 2003, 31: 3248-3256. 10.1093/nar/gkg410.PubMedPubMed CentralView ArticleGoogle Scholar
- Kulkarni A, Pavithra L, Rampalli S, Mogare D, Babu K, Shiekh G, Ghosh S, Chattopadhyay S: HIV-1 integration sites are flanked by potential MARs that alone can act as promoters. Biochem Biophys Res Commun. 2004, 322: 672-677. 10.1016/j.bbrc.2004.07.170.PubMedView ArticleGoogle Scholar
- Johnson CN, Levy LS: Matrix attachment regions as targets for retroviral integration. Virol J. 2005, 2: 68-10.1186/1743-422X-2-68.PubMedPubMed CentralView ArticleGoogle Scholar
- Kumar PP, Mehta S, Purbey PK, Notani D, Jayani RS, Purohit HJ, Raje DV, Ravi DS, Bhonde RR, Mitra D, Galande S: SATB1-binding sequences and Alu-like motifs define a unique chromatin context in the vicinity of human immunodeficiency virus type 1 integration sites. J Virol. 2007, 81: 5617-5627. 10.1128/JVI.01405-06.PubMedPubMed CentralView ArticleGoogle Scholar
- Welcsh PL, King MC: BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Genet. 2001, 10: 705-713. 10.1093/hmg/10.7.705.PubMedView ArticleGoogle Scholar
- Iarovaia OV, Shkumatov P, Razin SV: Breakpoint cluster regions of the AML-1 and ETO genes contain MAR elements and are preferentially associated with the nuclear matrix in proliferating HEL cells. J Cell Sci. 2004, 117: 4583-4590. 10.1242/jcs.01332.PubMedView ArticleGoogle Scholar
- Strick R, Zhang Y, Emmanuel N, Strissel PL: Common chromatin structures at breakpoint cluster regions may lead to chromosomal translocations found in chronic and acute leukemias. Hum Genet. 2006, 119: 479-495. 10.1007/s00439-006-0146-9.PubMedView ArticleGoogle Scholar
- Kleinjan DA, van Heyningen V: Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet. 2005, 76: 8-32. 10.1086/426833.PubMedPubMed CentralView ArticleGoogle Scholar
- Jackson JA, Trevino AV, Herzig MC, Herman TS, Woynarowski JM: Matrix attachment region (MAR) properties and abnormal expansion of AT island minisatellites in FRA16B fragile sites in leukemic CEM cells. Nucleic Acids Res. 2003, 31: 6354-6364. 10.1093/nar/gkg832.PubMedPubMed CentralView ArticleGoogle Scholar
- Woynarowski JM: AT-islands in fragile sites as scaffold/matrix-attachment regions (S/MARS). Fragile Sites: New Discoveries and Changing Perspectives. Edited by: Arrieta I, Penagarikano O, Télez M. 2007, New York: Nova Biomedical Books, 167-190.Google Scholar
- Woynarowski JM: AT islands - their nature and potential for anti-cancer strategies. Curr Cancer Drug Targets. 2004, 4: 219-234. 10.2174/1568009043481524.PubMedView ArticleGoogle Scholar
- Carter CA, Waud WR, Li LH, DeKoning TF, McGovren JP, Plowman J: Preclinical antitumor activity of bizelesin in mice. Clin Cancer Res. 1996, 2: 1143-1149.PubMedGoogle Scholar
- Alley MC, Hollingshead MG, Pacula-Cox CM, Waud WR, Hartley JA, Howard PW, Gregson SJ, Thurston DE, Sausville EA: SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations. Cancer Res. 2004, 64: 6700-6706. 10.1158/0008-5472.CAN-03-2942.PubMedView ArticleGoogle Scholar
- Zaidi SK, Young DW, Javed A, Pratap J, Montecino M, van Wijnen A, Lian JB, Stein JL, Stein GS: Nuclear microenvironments in biological control and cancer. Nat Rev Cancer. 2007, 7: 454-463. 10.1038/nrc2149.PubMedView ArticleGoogle Scholar
- Anachkova B, Djeliova V, Russev G: Nuclear matrix support of DNA replication. J Cell Biochem. 2005, 96: 951-961. 10.1002/jcb.20610.PubMedView ArticleGoogle Scholar