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• W2046191799 abstract "The centromere is a vital chromosomal structure that provides all living cells with the ability to faithfully partition their genetic material during mitotic and meiotic cell divisions. It functions by holding newly replicated sister chromatids together, allowing the attachment of spindle microtubules, and orchestrating the ordered movement of chromosomes to the daughter cells. The centromere has also been recognized as a “marshalling station” for a host of “passenger proteins” that appear transiently on the centromere during specific stages of the cell cycle (Earnshaw and MacKay, 1994Earnshaw WC MacKay AM Role of nonhistone proteins in the chromosomal events of mitosis.FASEB J. 1994; 8: 947-956Crossref PubMed Scopus (71) Google Scholar). Through the study of these and several of the known constitutive centromere proteins, diverse roles for these proteins have been defined, such as formation of centromere-specific chromatin, cohesion and release of sister chromatids, control of cell-cycle checkpoint, motor movement of chromosomes, modulation of spindle dynamics, organization of nuclear structure and intercellular bridge, and cytokinesis (reviewed by Earnshaw and MacKay, 1994Earnshaw WC MacKay AM Role of nonhistone proteins in the chromosomal events of mitosis.FASEB J. 1994; 8: 947-956Crossref PubMed Scopus (71) Google Scholar; Pluta et al., 1995Pluta AF Mackay AM Ainsztein AM Goldberg IG Earnshaw WC The centromere: hub of chromosomal activities.Science. 1995; 270: 1591-1594Crossref PubMed Scopus (298) Google Scholar; Choo, 1997Choo KHA The centromere. Oxford University Press, Oxford, New York, Tokyo1997Google Scholar). This review will focus on the unusual properties of the DNA that underlies centromere function and will discuss the implications of recent studies on neocentromeres, in light of our new understanding of the dynamic nature of the centromere DNA. All eukaryotic centromeres, except those of the budding yeast Saccharomyces cerevisiae, are known to contain a great abundance (as much as 5%–50% of each chromosome) of repeat DNA sequences. In humans, a typical centromere carries as many as 2,000–4,000 kb of a 171-bp repeat, known as “α-satellite” (e.g., see Tyler-Smith and Brown, 1987Tyler-Smith C Brown W Structure of the major block of alphoid satellite DNA on the human Y chromosome.J Mol Biol. 1987; 195: 457-470Crossref PubMed Scopus (128) Google Scholar; Wevrick and Willard, 1991Wevrick R Willard HF Physical map of the centromeric region of human chromosome 7: relationship between two distinct alpha satellite arrays.Nucleic Acids Res. 1991; 19: 2295-2301Crossref PubMed Scopus (77) Google Scholar; Jackson et al., 1993Jackson MS Slijepcevic P Ponder BAJ The organisation of repetitive sequences in the pericentromeric region of human chromosome 10.Nucleic Acids Res. 1993; 21: 5865-5874Crossref PubMed Scopus (20) Google Scholar; Trowell et al., 1993Trowell HE Nagy A Vissel B Choo KHA Long-range analyses of the centromeric regions of human chromosomes 13, 14 and 21: identification of a narrow domain containing two key centromeric DNA elements.Hum Mol Genet. 1993; 2: 1639-1649Crossref PubMed Scopus (74) Google Scholar). Several lines of evidence suggest that this DNA has a role in centromere function: (i) transfection of this DNA into cultured mammalian cells has shown that it confers centromere activity at the sites of DNA integration (Heartlein et al., 1988Heartlein MW Knoll JHM Latt SA Chromosome instability associated with human alphoid DNA transfected into the Chinese hamster genome.Mol Cell Biol. 1988; 8: 3611-3618PubMed Google Scholar; Haaf et al., 1992Haaf T Warburton PE Willard HF Integration of human alpha satellite DNA into simian chromosomes: centromere protein binding and disruption of normal chromosome segregation.Cell. 1992; 70: 681-696Abstract Full Text PDF PubMed Scopus (178) Google Scholar; Larin et al., 1994Larin Z Fricker MD Tyler-Smith C De novo formation of several features of a centromere following introduction of a Y alphoid YAC into mammalian cells.Hum Mol Genet. 1994; 3: 689-695Crossref PubMed Scopus (94) Google Scholar); (ii) analysis of rearranged (Tyler-Smith et al., 1993Tyler-Smith C Oakey RJ Larin Z Fisher RB Crocker M Affara NA Ferguson-Smith MA et al.Localization of DNA sequences required for human centromere function through an analysis of rearranged Y chromosomes.Nat Genet. 1993; 5: 368-375Crossref PubMed Scopus (136) Google Scholar) or in vitro–truncated (Brown et al., 1994Brown KE Barnett MA Burgtorf C Shaw P Buckle VJ Brown WR Dissecting the centromere of the human Y chromosome with cloned telomeric DNA.Hum Mol Genet. 1994; 3: 1227-1237Crossref PubMed Scopus (90) Google Scholar) Y chromosomes has demonstrated that retention of 150–200 kb of α-satellite is essential for centromere activity; and (iii) cotransfection of α-satellite with telomeric DNA and total human genomic DNA into human cell culture has resulted in the formation of a stable and independently segregating minichromosome (Harrington et al., 1997Harrington JJ Van Bokkelen G Mays RW Gustashaw K Willard HF Formation of de novo centromeres and construction of first-generation human artificial microchromosomes.Nat Genet. 1997; 15: 345-355Crossref PubMed Scopus (527) Google Scholar). However, conflicting evidence has come from observations in human dicentric chromosomes, in which this DNA is present on both the active centromere and the inactive centromere, suggesting that α-satellite per se does not confer centromere function (Earnshaw et al., 1989Earnshaw WC Ratrie III, H Stetten G Visualization of centromere proteins CENP-B and CENP-C on a stable dicentric chromosome in cytological spreads.Chromosoma. 1989; 98: 1-12Crossref PubMed Scopus (249) Google Scholar; Page et al., 1995Page SL Earnshaw WC Choo KHA Shaffer LG Further evidence that CENP-C is a necessary component of active centromeres: studies of a dic(X;15) with simultaneous immunofluorescence and FISH.Hum Mol Genet. 1995; 4: 289-294Crossref PubMed Scopus (69) Google Scholar; Sullivan and Schwartz, 1995Sullivan B Schwartz S Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres.Hum Mol Genet. 1995; 4: 2189-2197Crossref PubMed Scopus (180) Google Scholar). Moreover, an increasing number of stable human marker chromosomes (discussed below) have now been identified that lack detectable α-satellite, indicating that this DNA is not mandatory for centromere function. In other species, studies using a minichromosome in Drosophila have demonstrated that ∼200 kb of a simple, A/T-rich satellite DNA is important for centromere function and stable inheritance of the minichromosome (Murphy and Karpen, 1995Murphy TD Karpen GH Localization of centromere function in a Drosophila minichromosome.Cell. 1995; 82: 599-609Abstract Full Text PDF PubMed Scopus (162) Google Scholar). Similarly, investigation of the centromere DNA of the fission yeast Schizosaccharomyces pombe has indicated that a “K-type” repeat is essential for centromere function (Hahnenberger et al., 1991Hahnenberger KM Carbon J Clarke L Identification of DNA regions required for mitotic and meiotic functions within the centromere of Schizosaccharomyces pombe chromosome I.Mol Cell Biol. 1991; 11: 2206-2215Crossref PubMed Scopus (66) Google Scholar). In addition to these organisms, centromeric repeats from a wide range of organisms have now been isolated and characterized (reviewed by Choo, 1997Choo KHA The centromere. Oxford University Press, Oxford, New York, Tokyo1997Google Scholar). The analyses of these sequences (including those of the relatively simple, repeat DNA–free but A/T-rich, 125-bp centromeres of S. cerevisiae; Clarke and Carbon, 1985Clarke L Carbon J The structure and function of yeast centromeres.Annu Rev Genet. 1985; 19: 29-56Crossref PubMed Scopus (96) Google Scholar) have revealed a rather perplexing outcome, in that no discernible homology is seen between the centromeric DNA of the different species. This apparent lack of phylogenetic conservation of the DNA sequence of a structure that performs such a universal function as the centromere therefore seriously challenges conventional evolution dogma and highlights a “CEN-DNA paradox.” At present, the basis for this paradox is not fully understood, although some light is beginning to emerge from various recent studies described below. In recent years, an increasing number of supernumerary human marker chromosomes with centromeres that contain no detectable α-satellite have been reported. These “analphoid” marker chromosomes carry newly derived centromeres (or “neocentromeres”) that are apparently formed within interstitial chromosomal sites that have not previously been known to express centromere function. A well-characterized analphoid neocentromeric marker chromosome is the mardel(10) chromosome described by Voullaire et al., 1993Voullaire LE Slater HR Petrovic V Choo KHA A functional marker centromere with no detectable alpha-satellite, satellite III, or CENP-B protein: activation of a latent centromere?.Am J Hum Genet. 1993; 52: 1153-1163PubMed Google Scholar (fig. 1). This neocentromere forms a distinct primary constriction and is negative for α-satellite DNA, satellite 3 DNA (a simple repeat often found in the pericentric regions of human centromeres), CENPB (a functionally unknown centromere protein that binds a subset of α-satellite DNA), and C-banding (which detects repeat DNA–dense chromosomal regions, including all normal human centromeres). The marker chromosome is 100% stable in both short-term lymphocyte cultures and long-term cultures of fibroblast and lymphoblast cells, indicating that its neocentromere is fully functional in mitosis. The activity of this neocentromere is further revealed by the detection (duSart et al., 1997duSart D Cancilla MR Earle E Mao J Saffery R Tainton KM Kalitsis P et al.A functional neocentromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.Nat Genet. 1997; 16: 144-153Crossref PubMed Scopus (266) Google Scholar; E. Earle and K. H. A. Choo, unpublished data) of three functionally important centromere proteins: CENPA, CENPC, and CENPE. In other studies, CENPA has been shown to be a centromere-specific core histone that serves to differentiate the centromere from the rest of the chromosome, at the chromatin level (Sullivan et al., 1994Sullivan K Hechenberger M Masri K Human CENP-A contains a histone H3 related histone fold domain that is required for targeting to the centromere.J Cell Biol. 1994; 127: 581-592Crossref PubMed Scopus (349) Google Scholar); CENPC has been shown to be an essential centromeric protein for mitosis, as is evident from the inhibition of mitotic progression in cells microinjected with anti-CENPC antibodies (Bernat et al., 1990Bernat RL Borisy GG Rothfield NF Earnshaw WC Injection of anticentromere antibodies in interphase disrupts events required for chromosome movement in mitosis.J Cell Biol. 1990; 111: 1519-1533Crossref PubMed Scopus (118) Google Scholar; Tomkiel et al., 1994Tomkiel J Cooke CA Saitoh H Bernat RL Earnshaw WC CENP-C is required for maintaining proper kinetochore size and for a timely transition to anaphase.J Cell Biol. 1994; 125: 531-545Crossref PubMed Scopus (172) Google Scholar); and CENPE has been shown to be a motor molecule that is important for chromosome movement (Lombillo et al., 1995Lombillo VA Nislow C Yen TJ Gelfand VI McIntosh JR Antibodies to the kinesin motor domain and CENP-E inhibit microtubule depolymerization-dependent motion of chromosomes in vitro.J Cell Biol. 1995; 128: 107-115Crossref PubMed Scopus (193) Google Scholar; Thrower et al., 1995Thrower DA Jordan MA Schaar BT Yen TJ Wilson L Mitotic HeLa cells contain a CENP-E-associated minus end-directed microtubule motor.EMBO J. 1995; 14: 918-926Crossref PubMed Scopus (55) Google Scholar). In addition, CENPC and CENPE are known to associate with the active—but not with the inactive—centromeres of dicentric chromosomes (Earnshaw et al., 1989Earnshaw WC Ratrie III, H Stetten G Visualization of centromere proteins CENP-B and CENP-C on a stable dicentric chromosome in cytological spreads.Chromosoma. 1989; 98: 1-12Crossref PubMed Scopus (249) Google Scholar; Page et al., 1995Page SL Earnshaw WC Choo KHA Shaffer LG Further evidence that CENP-C is a necessary component of active centromeres: studies of a dic(X;15) with simultaneous immunofluorescence and FISH.Hum Mol Genet. 1995; 4: 289-294Crossref PubMed Scopus (69) Google Scholar; Sullivan and Schwartz, 1995Sullivan B Schwartz S Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres.Hum Mol Genet. 1995; 4: 2189-2197Crossref PubMed Scopus (180) Google Scholar). Maraschio et al., 1996Maraschio P Tupler R Rossi E Barbierato L Uccellatore F Rocchi M Zuffardi O et al.A novel mechanism for the origin of supernumerary marker chromosomes.Hum Genet. 1996; 97: 382-386Crossref PubMed Scopus (17) Google Scholar recently described a different case of a stable, chromosome 3–derived, analphoid marker chromosome that was formed through a rearrangement similar to that described for mardel(10). In addition, 16 other analphoid marker chromosomes, originating from 9 different chromosomes, have now been reported (fig. 2 and table 1). These marker chromosomes have been recognized through their lack of detectable α-satellite DNA and their C-band–negative nature. They are characterized by the formation of functional neocentromeres in chromosome regions that are not discernibly rearranged at the cytogenetic level. These neocentromeres have conferred to the marker chromosomes a significant, although sometimes variable, level of mitotic stability (see below). Where tested (markers M9-a, M10-c, M11-a, M13-a, M15-c, and M20-a), the neocentromeres, like that of mardel(10), demonstrated the presence of centromere protein(s) CENPC and/or CENPE, but not CENPB, although, in two cases (markers M8-a and M14-a), only the presence of some unspecified centromere proteins was reported, when anti-centromere antibodies derived from the sera of patients with the “CREST” form of autoimmune disease were used (Moroi et al., 1980Moroi Y Peebles C Fritzler M Steigerwald J Tan E Autoantibody to centromere (kinetochore) in scleroderma sera.Proc Natl Acad Sci USA. 1980; 77: 1627-1631Crossref PubMed Scopus (607) Google Scholar).Table 1Properties of Analphoid Marker Chromosomes Shown in Figure 2Stability of marker inbNA = not available. (%)Centromere ProteincA plus sign (+) denotes presence of the protein; and a minus sign (−) denotes absence of the protein. NA = not available.MarkerKaryotypeaInferred positions of putative neocentromeres are given.LymphocyteFibroblastLymphoblastCENPBOtherdCENPC, CENPE, or CREST (see text).ReferenceM2-a47,XY,del(2)(p11→p21),+der(2)(p11→[neocen]→p12)NA100NANANAPetit and Fryns, in pressPetit P, Fryns JP. Interstitial deletion 2p accompanied by marker chromosome formation of the deleted segment resulting in a stable acentric marker chromosome. Genet Couns (in press)Google ScholarM3-a47,XX,−3,+r(3)(p21.3→q25),+rea(3)(pter→p23[neocen]p23→p21.3::q25→qter)100100NANANAMaraschio et al., 1996Maraschio P Tupler R Rossi E Barbierato L Uccellatore F Rocchi M Zuffardi O et al.A novel mechanism for the origin of supernumerary marker chromosomes.Hum Genet. 1996; 97: 382-386Crossref PubMed Scopus (17) Google ScholarM8-a47,XX,+der(8)(pter→p23.1::p23.1→[neocen]→pter)100NANANA+Ohashi et al., 1994Ohashi H Wakui K Ogawa K Okano T Niikawa N Fukushima Y A stable acentric marker chromosome: possible existence of an intercalary ancient centromere at distal 8p.Am J Hum Genet. 1994; 55: 1202-1208PubMed Google ScholarM9-a47,XY,del(9)(p12),+der(9)(pter→p12::p12→[neocen]→pter)100NA100−+Vance et al., 1997Vance GH Curtis CA Heerema NA Schwartz S Palmer CG An apparently acentric marker chromosome originating from 9p with a functional centromere without detectable alpha and beta satellite sequences.Am J Med Genet. 1997; 71: 436-442Crossref PubMed Scopus (19) Google ScholarM9-b47,XY,+der(9)(pter→p21.2::p21.2→[neocen]→pter)100NANANANADepinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM10-a48,XY,−10,+rdel(10)(p11.2→q23.2), +mardel(10)(pter→p11.2::q23.2→q25.2[neocen]q25.2→qter),+bisatellited marker100100100−+Voullaire et al., 1993Voullaire LE Slater HR Petrovic V Choo KHA A functional marker centromere with no detectable alpha-satellite, satellite III, or CENP-B protein: activation of a latent centromere?.Am J Hum Genet. 1993; 52: 1153-1163PubMed Google ScholarM10-bdup(10)(qter→q11.2::q11.2→q26[neocen]q26→qter)90eDetected in leukemic cells of a patient with acute myeloid leukemia.NANANANAAbeliovich et al., 1996Abeliovich D Yehuda O Ben-Neriah S Kapelushnik Y Ben-Yehuda D Dup(10q) lacking alpha satellite DNA in bone marrow cells of a patient with acute myeloid leukemia.Cancer Genet Cytogenet. 1996; 89: 1-6Abstract Full Text PDF PubMed Scopus (24) Google ScholarM10-c47,XX,del(10)(q11→q23),+der(10)(q11→[neocen]→q23)6280NA−+Depinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM11-a47,XY,del(11)(q22),+der(11)(qter→q22::q22→[neocen]→qter)100100100−+Depinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM13-a47,XY,+der(13)(qter→q32::q32→[neocen]→qter)98832−+Depinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM14-a47,XX,del(14)(q32.1→qter),+der(14)(qter→q32.1::q32.1→[neocen]→qter)100NA100NA+Sacchi et al., 1996Sacchi N Magnani I Fuhrman-Conti AM Monard SP Darfler M A stable marker chromosome with a cryptic centromere: evidence for centromeric sequences associated with an inverted duplication.Cytogenet Cell Genet. 1996; 73: 123-129Crossref PubMed Scopus (22) Google ScholarM15-a47,XY,+der(15)(qter→q23::q23[neocen]q23→qter)70110NANABlennow et al., 1994Blennow E Telenius H de Vos D Larsson C Henriksson P Johansson O Carter NP et al.Tetrasomy 15q: two marker chromosomes with no detectable alpha-satellite DNA.Am J Hum Genet. 1994; 54: 877-883PubMed Google ScholarM15-b47,XX,+der(15)(qter→q24::q24[neocen]q24→qter)80NA0NANABlennow et al., 1994Blennow E Telenius H de Vos D Larsson C Henriksson P Johansson O Carter NP et al.Tetrasomy 15q: two marker chromosomes with no detectable alpha-satellite DNA.Am J Hum Genet. 1994; 54: 877-883PubMed Google ScholarM15-c47,XX,+der(15)(qter→q25.3::q25.3→[neocen]→qter)82NA33−+Depinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM15-d47,XY,+der(15)(qter→q25.3::q25.3→[neocen]→qter)74NA3NANADepinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM15-e47,XY,+der(15)(qter→q26.1::q26.1→[neocen]→qter)86NA0NANADepinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google ScholarM20-a47,XX,del(20)(p11.2),+der(20)(pter→p11.2::p11.2→p12[neocen]p12→pter)100100100−+L.E. Voullaire and K. H. A. Choo (unpublished data)MY-a45,X/46,XY/47,XY+mar(Y)(pter→psucen→q12[neocen]q12→qter)5NANANANABukvic et al., 1996Bukvic N Susca F Gentile M Tangari E Ianniruberto A Guanti G An unusual dicentric Y chromosome with a functional centromere with no detectable alpha-satellite.Hum Genet. 1996; 97: 453-456Crossref PubMed Scopus (36) Google Scholara Inferred positions of putative neocentromeres are given.b NA = not available.c A plus sign (+) denotes presence of the protein; and a minus sign (−) denotes absence of the protein. NA = not available.d CENPC, CENPE, or CREST (see text).e Detected in leukemic cells of a patient with acute myeloid leukemia. Open table in a new tab By far the most common mechanism for the formation of analphoid marker chromosomes is the de novo inverted duplication of some distal segments of chromosomes. This mechanism, which results in mirror-image chromosomes, accounts for 13 of the currently described markers (fig. 2). In 11 of these mirror-image chromosomes, the neocentromeres are found on one of the duplicated arms. In the remaining two cases (M15-a and M15-b), which were presented as metacentric chromosomes, the neocentromeres are at or near the breakpoints of the inverted duplications at 15q23 and 15q24, respectively. The inferred chromosomal structures of markers M2-a, M10-c, and MY-a are different from those depicted by the two mechanisms described above and are formed through different types of rearrangements (see the legend to fig. 2). In addition to these marker chromosomes, other, less well-characterized but stable analphoid markers, of undefined chromosomal origin and/or morphology, have been reported (Callen et al., 1992Callen DF Eyre H Yip M Freemantle J Haan EA Molecular cytogenetic and clinical studies of 42 patients with marker chromosomes.Am J Med Genet. 1992; 43: 709-715Crossref PubMed Scopus (102) Google Scholar; Crolla et al., 1992Crolla JA Dennis NR Jacobs PA A non-isotopic in situ hybridisation study of the chromosomal origin of 15 supernumerary marker chromosomes in man.J Med Genet. 1992; 29: 699-703Crossref PubMed Scopus (72) Google Scholar; Rauch et al., 1992Rauch A Pfeiffer RA Trautmann U Liehr T Rott HD Ulmer RA A study of ten small supernumerary (marker) chromosomes identified by fluorescence in situ hybridization (FISH).Clin Genet. 1992; 42: 84-90Crossref PubMed Scopus (75) Google Scholar). Only limited information on the time of formation of analphoid neocentromeric marker chromosomes is available. The mirror-image chromosome M10-b was reported as an acquired event found in the leukemic cells of a patient with acute myeloid leukemia (Abeliovich et al., 1996Abeliovich D Yehuda O Ben-Neriah S Kapelushnik Y Ben-Yehuda D Dup(10q) lacking alpha satellite DNA in bone marrow cells of a patient with acute myeloid leukemia.Cancer Genet Cytogenet. 1996; 89: 1-6Abstract Full Text PDF PubMed Scopus (24) Google Scholar). This suggests that the chromosome has a mitotic origin and that the steps leading to neocentromere formation can occur in cancerous cells. In addition to this marker, four other neocentromeric chromosomes have been studied by DNA polymorphism analyses (Depinet et al., 1997Depinet TW Zackowski JL Earnshaw WC Kaffe S Sekhon GS Stallard R Sullivan BA et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum Mol Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google Scholar). Three of these markers (M13-a, M15-c, and M15-e) have been shown to have a probable mitotic origin, whereas one (M15-d) appeared to be formed during meiosis. Further studies on the mitotic/meiotic origins of these and other neocentromeric marker chromosomes will be important for the understanding of the mechanisms underlying their formation. In total, ⩾11 different human chromosomes are now known to display neocentromeric activity (fig. 2 and table 1). The number of individual neocentromeric sites within the human genome is expected to be higher, since some of these chromosomes (e.g., chromosomes 10 and 15) have already been shown to contain multiple potential sites for such activity, and there seems no reason not to believe that this number will increase as new analphoid neocentromeric markers are reported. duSart et al., 1997duSart D Cancilla MR Earle E Mao J Saffery R Tainton KM Kalitsis P et al.A functional neocentromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.Nat Genet. 1997; 16: 144-153Crossref PubMed Scopus (266) Google Scholar investigated the DNA of the mardel(10) neocentromere. These workers employed centromere-specific anti-CENPA and anti-CENPC antibodies to tag the neocentromere. By chromosome walking using cloned single-copy normal DNA, an 80-kb region containing the core antibody-binding domain of the neocentromere was identified. Extensive restriction mapping (duSart et al., 1997duSart D Cancilla MR Earle E Mao J Saffery R Tainton KM Kalitsis P et al.A functional neocentromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.Nat Genet. 1997; 16: 144-153Crossref PubMed Scopus (266) Google Scholar) and high-density PCR analyses (M. R. Cancilla and K. H. A. Choo, unpublished data) of this core region indicated an identical genomic structure for the neocentromere and the corresponding normal chromosomal DNA at 10q25.2. These results, together with those of FISH studies reported, have indicated that the neocentromere DNA is specific to 10q25.2 and does not cross-hybridize with the DNA of the normal centromeres. The du Sart et al. study therefore provided direct molecular evidence that a previously noncentromeric region of the human genome is nonetheless capable of forming a neocentromere. On the basis of the existing data (Voullaire et al., 1993Voullaire LE Slater HR Petrovic V Choo KHA A functional marker centromere with no detectable alpha-satellite, satellite III, or CENP-B protein: activation of a latent centromere?.Am J Hum Genet. 1993; 52: 1153-1163PubMed Google Scholar; duSart et al., 1997duSart D Cancilla MR Earle E Mao J Saffery R Tainton KM Kalitsis P et al.A functional neocentromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.Nat Genet. 1997; 16: 144-153Crossref PubMed Scopus (266) Google Scholar), the most plausible explanation for the formation of a neocentromere at a hitherto noncentromeric chromosomal site in mardel(10) is that a “cryptic” or “latent” centromere becomes activated in situ within band 10q25.2 (fig. 1). Direct molecular evidence for the other neocentromeric marker chromosomes is eagerly awaited, but their cytogenetic and biochemical characteristics suggest that they too are formed through a similar mechanism involving latent-centromere activation. Furthermore, since all the known neocentromeres have originated from chromosomes' euchromatic regions (except for marker MY-a, which was formed within Yq12 heterochromatin) that are generally known to be chromosome specific, it can be inferred that the DNA sequences for these putative latent centromeres are different from one another. At present, the mechanism responsible for the activation of latent centromeres is not clear. Given that such a mechanism has the property of conferring heritable changes to otherwise identical DNA sequences, it must, by definition, be “epigenetic” in nature (Steiner and Clarke, 1994Steiner NC Clarke L A novel epigenetic effect can alter centromere function in fission yeast.Cell. 1994; 79: 865-874Abstract Full Text PDF PubMed Scopus (126) Google Scholar). This epigenetic mechanism would submit the centromere DNA—or the preferred active configuration of the centromeric DNA–protein complex—to a type of modification that is self-replicating. The nature of this modification is equally unknown, although mechanisms involving either methylation of centromeric DNA (Mitchell et al., 1996Mitchell AR Jeppesen P Nicol L Morrison H Kipling D Epigenetic control of mammalian centromere protein binding: does DNA methylation have a role?.J Cell Sci. 1996; 109: 2199-2206Crossref PubMed Google Scholar) or acetylation of centromeric chromatin (Allshire, 1997Allshire RC Centromeres, checkpoints and chromatid cohesion.Curr Opin Genet Dev. 1997; 7: 264-273Crossref PubMed Scopus (63) Google Scholar) have been proposed. This epigenetic modification may, besides its possible role in the formation of neocentromeres, also help control centromere activity in human dicentric chromosomes containing normal centromeres. It is generally assumed that true dicentrics with two active centromeres are rare, since they are unstable and prone to anaphase bridge formation and breakage due to forces generated by two active centromeres pulling the chromosomes toward opposite spindle poles. As such, most dicentric chromosomes are pseudodicentrics, in which one of the centromeres has become inactivated (e.g., see Earnshaw et al., 1989Earnshaw WC Ratrie III, H Stetten G Visualization of centromere proteins CENP-B and CENP-C on a stable dicentric chromosome in cytological spreads.Chromosoma. 1989; 98: 1-12Crossref PubMed Scopus (249) Google Scholar; Therman and Susman, 1993Therman E Susman M Human chromosomes—structure, behavior, and effects. 3d ed. Springer, New York1993Google Scholar; Page et al., 1995Page SL Earnshaw WC Choo KHA Shaffer LG Further evidence that CENP-C is a necessary component of ac" @default.
• W2046191799 created "2016-06-24" @default.
• W2046191799 creator A5000135579 @default.
• W2046191799 date "1997-12-01" @default.
• W2046191799 modified "2023-10-09" @default.
• W2046191799 title "Centromere DNA Dynamics: Latent Centromeres and Neocentromere Formation" @default.
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