The spindle assembly checkpoint suspends cell cycle progression if improperly aligned chromosomes are detected at metaphase. Evolutionarily conserved kinetochore-associated proteins are believed to be key elements of this regulatory pathway. A breakdown in checkpoint function could bring about genomic instability, which may be responsible for the prevalence of aneuploidy in oocytes of older women. Maternal aging remains the overwhelming factor in the etiology of human aneuploidy in assisted reproduction. Defects in cell cycle checkpoint genes may play a role in its development. The existence of such monitoring mechanisms in oocytes has long been controversial. Studies providing evidence in support of and against their existence are reviewed.   

1.
Basto R, Gomes R, Karess RE: Rough deal and Zw10 are required for the metaphase checkpoint in Drosophila. Nat Cell Biol 2:939–943 (2000).
2.
Bauld R, Sutherland GR, Bain AD: Chromosome studies in investigation of stillbirths and neonatal deaths. Arch Dis Child 49:782–788 (1974).
3.
Brady DM, Hardwick KG: Complex formation between Mad1p, Bub1p and Bub3p is crucial for spindle checkpoint function. Curr Biol 10:675–678 (2000).
4.
Brunet S, Pahlavan G, Taylor S, Maro B: Functionality of the spindle checkpoint during the first meiotic division of mammalian oocytes. Reproduction 126:443–450 (2003).
5.
Chan GK, Jablonski SA, Sudakin V, Hittle JC, Yen TJ: Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosomes/APC. J Cell Biol 146:941–954 (1999).
6.
Chen RH, Murray A: Characterization of spindle assembly checkpoint in Xenopus egg extracts. Methods Enzymol 283:572–584 (1997).
7.
Cleveland DW, Mao Y, Sullivan KF: Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112:407–421 (2003).
8.
Dailey T, Dale B, Cohen J, Munne S: Association between nondisjunction and maternal age in meiosis-II human oocytes. Am J Hum Genet 59:176–184 (1996).
9.
Dobles M, Liberal V, Scott ML, Benezra R, Sorger PK: Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101:635–645 (2000).
10.
Eichenlaub-Ritter U, Betzendahl I: Chloral hydrate induced spindle aberrations, metaphase I arrest and aneuploidy in mouse oocytes. Mutagenesis 10:477–486 (1995).
11.
Fulka J Jr, Moor RM, Fulka J: Sister chromatid separation and the metaphase-anaphase transition in mouse oocytes. Dev Biol 165:410–417 (1994).
12.
Fulka J Jr, Moor RM, Fulka J: Mouse oocyte maturation: meiotic checkpoints. Exp Cell Res 219:414–419 (1995a).
13.
Fulka J Jr, Moor RM, Fulka J: Replicating DNA does not block germinal vesicle breakdown in mouse oocytes. J Exp Zool 272:245–248 (1995b).
14.
Fulka J Jr, Kalab P, First NL, Moor RM: Damaged chromatin does not prevent the exit from metaphase I in fused mouse oocytes. Hum Reprod 12:2473–2476 (1997).
15.
Ghabrial A, Schupbach T: Activation of meiotic checkpoint regulates translation of gurken during Drosophila oogenesis. Nat Cell Biol 1:354–357 (1999).
16.
Gorbsky GJ: Cell cycle checkpoint: arresting progress in mitosis. Bioessays 19:193–197 (1997).
17.
Hagting A, den Elzen N, Vodermaier HC, Waizenegger IC, Peters J-M, Pines J: Human securing proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J Cell Biol 157:1125–1137 (2002).
18.
Hardwick KG: The spindle checkpoint. Trends Genet 14:1–4 (1998).
19.
Hartwell L: Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71:543–546 (1992).
20.
Hartwell LH, Weinert TA: Checkpoints: controls that ensure the order of cell cycle events. Science 246:629–634 (1989).
21.
Hassold T, Sherman S: Down syndrome: genetic recombination and the origin of the extra chromosome 21. Clin Genet 57:95–100 (2000).
22.
Jablonski SA, Chan GKT, Cooke CA, Earnshaw WC, Yen TJ: The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis. Chromosoma 107:386–396 (1998).
23.
LeMaire-Adkins R, Radke K, Hunt PA: Lack of checkpoint control at the metaphase/anaphase transition: a mechanism of meiotic nondisjunction in mammalian females. J Cell Biol 139:1611–1619 (1997).
24.
Li R, Murray AW: Feedback control of mitosis in budding yeast. Cell 66:519–531 (1991).
25.
Li Y, Benezra R: Identification of human mitotic checkpoint gene: hsMAD2. Science 274:246–248 (1996).
26.
Li Y, Gorbea C, Mahaffey D, Rechsteiner M, Benezra R: MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci USA 94:12431–12436 (1997).
27.
Liu L, Keefe DL: Ageing-associated aberration I meiosis of oocytes from senescence-accelerated mice. Hum Reprod 17:2678–2685 (2002).
28.
Liu L, Keefe DL: Nuclear origin of aging-associated meiotic defects in senescence-accelerated mice. Biol Reprod 71:1724–1729 (2004).
29.
Luo X, Fang G, Coldiron M, Lin Y, Yu H, Kirschner MW, Wagner G: Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol 7:224–229 (2000).
30.
Michel L, Diaz-Rodriguez E, Narayan G, Hernando E, Vundavalli V, Murty VS: Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci USA 101:4459–4464 (2004).
31.
Nicklas RB, Campbell MS, Ward SC, Gorbsky GJ: Tension-sensitive kinetochore phosphorylation in vitro. J Cell Sci 111:3189–3196 (1998).
32.
Ouyang B, Lan Z, Meadows J, Pan H, Fukasawa K, Li W, Dai W: Human Bub1: a putative spindle checkpoint kinase closely linked to cell proliferation. Cell Growth Differ 9:877–885 (1998).
33.
Rieder CL, Cole RW, Khodjakov A, Sluder G: The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol 130:941–948 (1995).
34.
Rieder CL, Khodjakov A, Paliulis LV, Fortier TM, Cole RW, Sluder G: Mitosis in vertebrate somatic cells with two spindles: Implications for the metaphase/anaphase transition checkpoint and cleavage. Proc Natl Acad Sci USA 94:5107–5112 (1997).
35.
Shonn MA, McCarroll R, Murray AW: Requirement of the spindle checkpoint for proper chromosome segregation in budding yeast meiosis. Science 289:300–303 (2000).
36.
Shonn MA, Murray AL, Murray AW: Spindle checkpoint component Mad2 contributes to biorientation of homologous chromosomes. Curr Biol 13:1979–1984 (2003).
37.
Skoufias DA, Andreassen PR, Lacroix FB, Wilson L, Margolis RL: Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochores-tension checkpoints. Proc Natl Acad Sci USA 98:4492–4497 (2001).
38.
Sluder G, McCollum D: The mad ways of meiosis. Science 289:254–256 (2000).
39.
Steuerwald N, Cohen J, Herrera RJ, Brenner CA: Analysis of gene expression in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR. Mol Hum Reprod 5:1034–1039 (1999).
40.
Steuerwald N, Cohen J, Herrera R, Brenner CA: Quantification of mRNA in single oocytes and embryos by real-time rapid cycle fluorescence monitored RT-PCR. Mol Hum Reprod 6:448–453 (2000).
41.
Steuerwald N, Cohen J, Herrera R, Sandalinas M, Brenner CA: Association between spindle assembly checkpoint expression and maternal age in human oocytes. Mol Hum Reprod 7:49–55 (2001).
42.
Straight AF: Cell cycle: checkpoint proteins and kinetochores. Curr Biol 7:R613–R616 (1997).
43.
Taylor SS, McKeon F: Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89:727–735 (1997).
44.
Taylor SS, Hussein D, Wang Y, Elderkin S, Morrow CJ: Kinetochore localization and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells. J Cell Sci 114:4385–4395 (2001).
45.
Wassmann K, Niault T, Maro B: Metaphase I arrest upon activation of the Mad2-dependent spindle checkpoint in mouse oocytes. Curr Biol 13:1596–1608 (2003).
46.
Waters JC, Chen R-H, Murray AW, Salmon ED: Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J Cell Biol 141:1181–1191 (1998).
47.
Weiss E, Winey M: The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint. J Cell Biol 132:111–123 (1996).
48.
Woods LM, Hodges CA, Baart E, Baker SM, Liskay M, Hunt PA: Chromosomal influence on meiotic spindle assembly: abnormal meiosis I in female Mlh1 mutant mice. J Cell Biol 145:1395–1406 (1999).
49.
Yin H, Cukurcam S, Betzendahl I, Adler ID, Eichenlaub-Ritter U: Trichlorfon exposure, spindle aberrations and nondisjunction in mammalian oocytes. Chromosoma 107:514–522 (1998).
50.
Zhang D, Ma W, Li Y-H, Hou Y, Li SW, Meng XQ, et al: Intra-oocyte localization of MAD2 and its relationship with kinetochores, microtubules, and chromosomes in rat oocytes during meiosis. Biol Reprod 71:740–748 (2004).
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