Abstract
Micronuclei, small DNA-containing structures separate from the main nucleus, were used for decades as an indicator of genotoxic damage. Micronuclei containing whole chromosomes were considered a biomarker of aneuploidy and were believed to form, upon mitotic exit, from chromosomes that lagged behind in anaphase as all other chromosomes segregated to the poles of the mitotic spindle. However, the mechanism responsible for inducing anaphase lagging chromosomes remained unknown until just over twenty years ago. Here, I summarize what preceded and what followed this discovery, highlighting some of the open questions and opportunities for future investigation.
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References
Akiyoshi B, Sarangapani KK, Powers AF, Nelson CR, Reichow SL, Arellano-Santoyo H, Gonen T, Ranish JA, Asbury CL, Biggins S (2010) Tension directly stabilizes reconstituted kinetochore-microtubule attachments. Nature 468:576–579. https://doi.org/10.1038/nature09594
Andrews PD, Ovechkina Y, Morrice N, Wagenbach M, Duncan K, Wordeman L, Swedlow JR (2004) Aurora B regulates MCAK at the mitotic centromere. Dev Cell 6:253–268. https://doi.org/10.1016/s1534-5807(04)00025-5
Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E, Cuartas I, Redondo-Campos S, Folch G, Gonzalez-Junca A, Sodir NM, Masso-Valles D, Beaulieu ME, Swigart LB, Mc Gee MM, Somma MP, Nasi S, Seoane J, Evan GI, Soucek L (2014) Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat Commun 5:4632. https://doi.org/10.1038/ncomms5632
Antoccia A, Degrassi F, Battistoni A, Ciliutti P, Tanzarella C (1991) In vitro micronucleus test with kinetochore staining: evaluation of test performance. Mutagenesis 6:319–324. https://doi.org/10.1093/mutage/6.4.319
Bakhoum SF, Danilova OV, Kaur P, Levy NB, Compton DA (2011) Chromosomal instability substantiates poor prognosis in patients with diffuse large B-cell lymphoma. Clin Cancer Res 17:7704–7711. https://doi.org/10.1158/1078-0432.CCR-11-2049
Bakhoum SF, Genovese G, Compton DA (2009a) Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr Biol 19:1937–1942. https://doi.org/10.1016/j.cub.2009.09.055
Bakhoum SF, Kabeche L, Wood MD, Laucius CD, Qu D, Laughney AM, Reynolds GE, Louie RJ, Phillips J, Chan DA, Zaki BI, Murnane JP, Petritsch C, Compton DA (2015) Numerical chromosomal instability mediates susceptibility to radiation treatment. Nat Commun 6:5990. https://doi.org/10.1038/ncomms6990
Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe’er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC (2018) Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553:467–472. https://doi.org/10.1038/nature25432
Bakhoum SF, Silkworth WT, Nardi IK, Nicholson JM, Compton DA, Cimini D (2014) The mitotic origin of chromosomal instability. Curr Biol 24:R148-149. https://doi.org/10.1016/j.cub.2014.01.019
Bakhoum SF, Thompson SL, Manning AL, Compton DA (2009b) Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat Cell Biol 11:27–35. https://doi.org/10.1038/ncb1809
Baudoin NC, Cimini D (2018a) Chromosome Segregation: The Bigger They Come, the Harder They Fall. Curr Biol 28:R665–R667. https://doi.org/10.1016/j.cub.2018.04.036
Baudoin NC, Cimini D (2018b) A guide to classifying mitotic stages and mitotic defects in fixed cells. Chromosoma 127:215–227. https://doi.org/10.1007/s00412-018-0660-2
Biggins S, Severin FF, Bhalla N, Sassoon I, Hyman AA, Murray AW (1999) The conserved protein kinase Ipl1 regulates microtubule binding to kinetochores in budding yeast. Genes Dev 13:532–544. https://doi.org/10.1101/gad.13.5.532
Bochtler T, Kartal-Kaess M, Granzow M, Hielscher T, Cosenza MR, Herold-Mende C, Jauch A, Kramer A (2019) Micronucleus formation in human cancer cells is biased by chromosome size. Genes Chromosomes Cancer 58:392–395. https://doi.org/10.1002/gcc.22707
Bolhaqueiro ACF, Ponsioen B, Bakker B, Klaasen SJ, Kucukkose E, van Jaarsveld RH, Vivie J, Verlaan-Klink I, Hami N, Spierings DCJ, Sasaki N, Dutta D, Boj SF, Vries RGJ, Lansdorp PM, van de Wetering M, van Oudenaarden A, Clevers H, Kranenburg O, Foijer F, Snippert HJG, Kops G (2019) Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nat Genet 51:824–834. https://doi.org/10.1038/s41588-019-0399-6
Bonassi S, Coskun E, Ceppi M, Lando C, Bolognesi C, Burgaz S, Holland N, Kirsh-Volders M, Knasmueller S, Zeiger E, Carnesoltas D, Cavallo D, da Silva J, de Andrade VM, Demircigil GC, Dominguez Odio A, Donmez-Altuntas H, Gattas G, Giri A, Giri S, Gomez-Meda B, Gomez-Arroyo S, Hadjidekova V, Haveric A, Kamboj M, Kurteshi K, Martino-Roth MG, Montero Montoya R, Nersesyan A, Pastor-Benito S, Favero Salvadori DM, Shaposhnikova A, Stopper H, Thomas P, Torres-Bugarin O, Yadav AS, Zuniga Gonzalez G, Fenech M (2011a) The HUman MicroNucleus project on eXfoLiated buccal cells (HUMN(XL)): the role of life-style, host factors, occupational exposures, health status, and assay protocol. Mutat Res 728:88–97. https://doi.org/10.1016/j.mrrev.2011.06.005
Bonassi S, El-Zein R, Bolognesi C, Fenech M (2011b) Micronuclei frequency in peripheral blood lymphocytes and cancer risk: evidence from human studies. Mutagenesis 26:93–100. https://doi.org/10.1093/mutage/geq075
Bonatti S, Cavalieri Z, Viaggi S, Abbondandolo A (1992) The analysis of 10 potential spindle poisons for their ability to induce CREST-positive micronuclei in human diploid fibroblasts. Mutagenesis 7:111–114. https://doi.org/10.1093/mutage/7.2.111
Brinkley BR (2001) Managing the centrosome numbers game: from chaos to stability in cancer cell division. Trends Cell Biol 11:18–21. https://doi.org/10.1016/s0962-8924(00)01872-9
Broad AJ, DeLuca JG (2020) The right place at the right time: Aurora B kinase localization to centromeres and kinetochores. Essays Biochem 64:299–311. https://doi.org/10.1042/EBC20190081
Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G (2012) Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 30:413–421. https://doi.org/10.1038/nbt.2203
Catalan J, Falck GC, Norppa H (2000) The X chromosome frequently lags behind in female lymphocyte anaphase. Am J Hum Genet 66:687–691. https://doi.org/10.1086/302769
Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A (2006) The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127:983–997. https://doi.org/10.1016/j.cell.2006.09.039
Chen GY, Renda F, Zhang H, Gokden A, Wu DZ, Chenoweth DM, Khodjakov A, Lampson MA (2021) Tension promotes kinetochore-microtubule release by Aurora B kinase. J Cell Biol 22010.1083/jcb.202007030
Cheng JM, Li J, Tang JX, Hao XX, Wang ZP, Sun TC, Wang XX, Zhang Y, Chen SR, Liu YX (2017) Merotelic kinetochore attachment in oocyte meiosis II causes sister chromatids segregation errors in aged mice. Cell Cycle 16:1404–1413. https://doi.org/10.1080/15384101.2017.1327488
Ciferri C, Pasqualato S, Screpanti E, Varetti G, Santaguida S, Dos Reis G, Maiolica A, Polka J, De Luca JG, De Wulf P, Salek M, Rappsilber J, Moores CA, Salmon ED, Musacchio A (2008) Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex. Cell 133:427–439. https://doi.org/10.1016/j.cell.2008.03.020
Cimini D, Antoccia A, Tanzarella C, Degrassi F (1997) Topoisomerase II inhibition in mitosis produces numerical and structural chromosomal aberrations in human fibroblasts. Cytogenet Cell Genet 76:61–67. https://doi.org/10.1159/000134517
Cimini D, Cameron LA, Salmon ED (2004) Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr Biol 14:2149–2155. https://doi.org/10.1016/j.cub.2004.11.029
Cimini D, Fioravanti D, Salmon ED, Degrassi F (2002) Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells. J Cell Sci 115:507–515. https://doi.org/10.1242/jcs.115.3.507
Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED (2001) Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J Cell Biol 153:517–527. https://doi.org/10.1083/jcb.153.3.517
Cimini D, Moree B, Canman JC, Salmon ED (2003) Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms. J Cell Sci 116:4213–4225. https://doi.org/10.1242/jcs.00716
Cimini D, Tanzarella C, Degrassi F (1999) Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14:563–568. https://doi.org/10.1093/mutage/14.6.563
Cimini D, Wan X, Hirel CB, Salmon ED (2006) Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol 16:1711–1718. https://doi.org/10.1016/j.cub.2006.07.022
Cortes-Ciriano I, Lee JJ, Xi R, Jain D, Jung YL, Yang L, Gordenin D, Klimczak LJ, Zhang CZ, Pellman DS, Group PSVW, Park PJ, Consortium P (2020) Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat Genet 52:331–341. https://doi.org/10.1038/s41588-019-0576-7
Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D (2012) DNA breaks and chromosome pulverization from errors in mitosis. Nature 482:53–58. https://doi.org/10.1038/nature10802
de Regt AK, Clark CJ, Asbury CL, Biggins S (2022) Tension can directly suppress Aurora B kinase-triggered release of kinetochore-microtubule attachments. Nat Commun 13:2152. https://doi.org/10.1038/s41467-022-29542-8
Degrassi F, Tanzarella C (1988) Immunofluorescent staining of kinetochores in micronuclei: a new assay for the detection of aneuploidy. Mutat Res 203:339–345. https://doi.org/10.1016/0165-1161(88)90030-1
DeLuca JG, Gall WE, Ciferri C, Cimini D, Musacchio A, Salmon ED (2006) Kinetochore microtubule dynamics and attachment stability are regulated by Hec1. Cell 127:969–982. https://doi.org/10.1016/j.cell.2006.09.047
Deng C, Ya A, Compton DA, Godek KM (2023) A pluripotent developmental state confers a low fidelity of chromosome segregation. Stem Cell Reports 18:475–488. https://doi.org/10.1016/j.stemcr.2022.12.008
Drpic D, Almeida AC, Aguiar P, Renda F, Damas J, Lewin HA, Larkin DM, Khodjakov A, Maiato H (2018) Chromosome Segregation Is Biased by Kinetochore Size. Curr Biol 28:1344-1356 e1345. https://doi.org/10.1016/j.cub.2018.03.023
Falck GC, Catalan J, Norppa H (2002) Nature of anaphase laggards and micronuclei in female cytokinesis-blocked lymphocytes. Mutagenesis 17:111–117. https://doi.org/10.1093/mutage/17.2.111
Fenech M (2000) The in vitro micronucleus technique. Mutat Res 455:81–95. https://doi.org/10.1016/s0027-5107(00)00065-8
Fenech M, Knasmueller S, Bolognesi C, Holland N, Bonassi S, Kirsch-Volders M (2020) Micronuclei as biomarkers of DNA damage, aneuploidy, inducers of chromosomal hypermutation and as sources of pro-inflammatory DNA in humans. Mutat Res Rev Mutat Res 786:108342. https://doi.org/10.1016/j.mrrev.2020.108342
Fenech M, Morley AA (1989) Kinetochore detection in micronuclei: an alternative method for measuring chromosome loss. Mutagenesis 4:98–104. https://doi.org/10.1093/mutage/4.2.98
Ferrandiz N, Downie L, Starling GP, Royle SJ (2022) Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes. J Cell Biol 22110.1083/jcb.202203021
Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D (2005) Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043–1047
Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. Nature 460:278–282. https://doi.org/10.1038/nature08136
Giaretti W (1997) Aneuploidy mechanisms in human colorectal preneoplastic lesions and Barrett’s esophagus. Is there a role for K-ras and p53 mutations? Anal Cell Pathol 15:99–117. https://doi.org/10.1155/1997/264135
Gisselsson D, Bjork J, Hoglund M, Mertens F, Dal Cin P, Akerman M, Mandahl N (2001) Abnormal nuclear shape in solid tumors reflects mitotic instability. Am J Pathol 158:199–206. https://doi.org/10.1016/S0002-9440(10)63958-2
Gisselsson D, Palsson E, Yu C, Mertens F, Mandahl N (2004) Mitotic instability associated with late genomic changes in bone and soft tissue tumours. Cancer Lett 206:69–76. https://doi.org/10.1016/j.canlet.2003.10.022
Gomes AM, Orr B, Novais-Cruz M, De Sousa F, Macario-Monteiro J, Lemos C, Ferras C, Maiato H (2022) Micronuclei from misaligned chromosomes that satisfy the spindle assembly checkpoint in cancer cells. Curr Biol 32:4240-4254 e4245. https://doi.org/10.1016/j.cub.2022.08.026
Gregan J, Polakova S, Zhang L, Tolic-Norrelykke IM, Cimini D (2011) Merotelic kinetochore attachment: causes and effects. Trends Cell Biol 21:374–381. https://doi.org/10.1016/j.tcb.2011.01.003
Gregan J, Riedel CG, Pidoux AL, Katou Y, Rumpf C, Schleiffer A, Kearsey SE, Shirahige K, Allshire RC, Nasmyth K (2007) The kinetochore proteins Pcs1 and Mde4 and heterochromatin are required to prevent merotelic orientation. Curr Biol 17:1190–1200. https://doi.org/10.1016/j.cub.2007.06.044
Gronroos E, Lopez-Garcia C (2018) Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities. Cancer Res 78:6529–6535. https://doi.org/10.1158/0008-5472.CAN-18-1958
Gustavino B, Degrassi F, Filipponi R, Modesti D, Tanzarella C, Rizzoni M (1994) Mitotic indirect non-disjunction in phytohemagglutinin stimulated human lymphocytes. Mutagenesis 9:17–21. https://doi.org/10.1093/mutage/9.1.17
Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA (2017) Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548:466–470. https://doi.org/10.1038/nature23470
Hatch EM, Fischer AH, Deerinck TJ, Hetzer MW (2013) Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154:47–60. https://doi.org/10.1016/j.cell.2013.06.007
He B, Gnawali N, Hinman AW, Mattingly AJ, Osimani A, Cimini D (2019) Chromosomes missegregated into micronuclei contribute to chromosomal instability by missegregating at the next division. Oncotarget 10:2660–2674. https://doi.org/10.18632/oncotarget.26853
Hennig UG, Rudd NL, Hoar DI (1988) Kinetochore immunofluorescence in micronuclei: a rapid method for the in situ detection of aneuploidy and chromosome breakage in human fibroblasts. Mutat Res 203:405–414. https://doi.org/10.1016/0165-1161(88)90013-1
Hoffelder DR, Luo L, Burke NA, Watkins SC, Gollin SM, Saunders WS (2004) Resolution of anaphase bridges in cancer cells. Chromosoma 112:389–397. https://doi.org/10.1007/s00412-004-0284-6
Hogstedt B, Karlsson A (1985) The size of micronuclei in human lymphocytes varies according to inducing agent used. Mutat Res 156:229–232. https://doi.org/10.1016/0165-1218(85)90067-9
Holubcova Z, Blayney M, Elder K, Schuh M (2015) Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. Science 348:1143–1147. https://doi.org/10.1126/science.aaa9529
Janicke MA, LaFountain JR Jr (1984) Malorientation in half-bivalents at anaphase: analysis of autosomal laggards in untreated, cold-treated, and cold-recovering crane fly spermatocytes. J Cell Biol 98:859–869. https://doi.org/10.1083/jcb.98.3.859
Janicke MA, Lasko L, Oldenbourg R, LaFountain JR Jr (2007) Chromosome malorientations after meiosis II arrest cause nondisjunction. Mol Biol Cell 18:1645–1656. https://doi.org/10.1091/mbc.e06-10-0963
Kaseda K, McAinsh AD, Cross RA (2012) Dual pathway spindle assembly increases both the speed and the fidelity of mitosis. Biol Open 1:12–18. https://doi.org/10.1242/bio.2011012
Kato H, Sandberg AA (1968) Chromosome pulverization in human cells with micronuclei. J Natl Cancer Inst 40:165–179
Khodjakov A, Cole RW, McEwen BF, Buttle KF, Rieder CL (1997) Chromosome fragments possessing only one kinetochore can congress to the spindle equator. J Cell Biol 136:229–240. https://doi.org/10.1083/jcb.136.2.229
Klaasen SJ, Truong MA, van Jaarsveld RH, Koprivec I, Stimac V, de Vries SG, Risteski P, Kodba S, Vukusic K, de Luca KL, Marques JF, Gerrits EM, Bakker B, Foijer F, Kind J, Tolic IM, Lens SMA, Kops G (2022) Nuclear chromosome locations dictate segregation error frequencies. Nature 607:604–609. https://doi.org/10.1038/s41586-022-04938-0
Kline-Smith SL, Khodjakov A, Hergert P, Walczak CE (2004) Depletion of centromeric MCAK leads to chromosome congression and segregation defects due to improper kinetochore attachments. Mol Biol Cell 15:1146–1159. https://doi.org/10.1091/mbc.e03-08-0581
Knowlton AL, Lan W, Stukenberg PT (2006) Aurora B is enriched at merotelic attachment sites, where it regulates MCAK. Curr Biol 16:1705–1710. https://doi.org/10.1016/j.cub.2006.07.057
Kouznetsova A, Hernandez-Hernandez A, Hoog C (2014) Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes. Nat Commun 5:4409. https://doi.org/10.1038/ncomms5409
Kouznetsova A, Kitajima TS, Brismar H, Hoog C (2019) Post-metaphase correction of aberrant kinetochore-microtubule attachments in mammalian eggs. EMBO Rep 20:e47905. https://doi.org/10.15252/embr.201947905
Kreis NN, Sanhaji M, Rieger MA, Louwen F, Yuan J (2014) p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells. Oncogene 33:5716–5728. https://doi.org/10.1038/onc.2013.518
Krupina K, Goginashvili A, Cleveland DW (2021) Causes and consequences of micronuclei. Curr Opin Cell Biol 70:91–99. https://doi.org/10.1016/j.ceb.2021.01.004
Ladrach KS, LaFountain JR Jr (1986) Malorientation and abnormal segregation of chromosomes during recovery from colcemid and nocodazole. Cell Motil Cytoskeleton 6:419–427. https://doi.org/10.1002/cm.970060407
Lan W, Zhang X, Kline-Smith SL, Rosasco SE, Barrett-Wilt GA, Shabanowitz J, Hunt DF, Walczak CE, Stukenberg PT (2004) Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity. Curr Biol 14:273–286. https://doi.org/10.1016/j.cub.2004.01.055
Lara-Gonzalez P, Pines J, Desai A (2021) Spindle assembly checkpoint activation and silencing at kinetochores. Semin Cell Dev Biol 117:86–98. https://doi.org/10.1016/j.semcdb.2021.06.009
Lengauer C, Kinzler KW, Vogelstein B (1997) Genetic instability in colorectal cancers. Nature 386:623–627. https://doi.org/10.1038/386623a0
Littler S, Sloss O, Geary B, Pierce A, Whetton AD, Taylor SS (2019) Oncogenic MYC amplifies mitotic perturbations. Open Biol 9:190136. https://doi.org/10.1098/rsob.190136
Liu S, Kwon M, Mannino M, Yang N, Renda F, Khodjakov A, Pellman D (2018) Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561:551–555. https://doi.org/10.1038/s41586-018-0534-z
Ly P, Brunner SF, Shoshani O, Kim DH, Lan W, Pyntikova T, Flanagan AM, Behjati S, Page DC, Campbell PJ, Cleveland DW (2019) Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat Genet 51:705–715. https://doi.org/10.1038/s41588-019-0360-8
Ly P, Teitz LS, Kim DH, Shoshani O, Skaletsky H, Fachinetti D, Page DC, Cleveland DW (2017) Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nat Cell Biol 19:68–75. https://doi.org/10.1038/ncb3450
Maciejowski J, Hatch EM (2020) Nuclear Membrane Rupture and Its Consequences. Annu Rev Cell Dev Biol 36:85–114. https://doi.org/10.1146/annurev-cellbio-020520-120627
Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T (2015) Chromothripsis and Kataegis Induced by Telomere Crisis. Cell 163:1641–1654. https://doi.org/10.1016/j.cell.2015.11.054
Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, Olova N, Sutcliffe H, Rainger JK, Leitch A, Osborn RT, Wheeler AP, Nowotny M, Gilbert N, Chandra T, Reijns MAM, Jackson AP (2017) cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548:461–465. https://doi.org/10.1038/nature23449
Maddox P, Straight A, Coughlin P, Mitchison TJ, Salmon ED (2003) Direct observation of microtubule dynamics at kinetochores in Xenopus extract spindles: implications for spindle mechanics. J Cell Biol 162:377–382. https://doi.org/10.1083/jcb.200301088
Maiato H, Silva S (2023) Double-checking chromosome segregation. J Cell Biol 22210.1083/jcb.202301106
Mammel AE, Huang HZ, Gunn AL, Choo E, Hatch EM (2022) Chromosome length and gene density contribute to micronuclear membrane stability. Life Sci Alliance 510.26508/lsa.202101210
Maney T, Hunter AW, Wagenbach M, Wordeman L (1998) Mitotic centromere-associated kinesin is important for anaphase chromosome segregation. J Cell Biol 142:787–801. https://doi.org/10.1083/jcb.142.3.787
Mihajlovic AI, Haverfield J, FitzHarris G (2021) Distinct classes of lagging chromosome underpin age-related oocyte aneuploidy in mouse. Dev Cell 56:2273-2283 e2273. https://doi.org/10.1016/j.devcel.2021.07.022
Moroi Y, Peebles C, Fritzler MJ, Steigerwald J, Tan EM (1980) Autoantibody to centromere (kinetochore) in scleroderma sera. Proc Natl Acad Sci U S A 77:1627–1631. https://doi.org/10.1073/pnas.77.3.1627
Nam HJ, van Deursen JM (2014) Cyclin B2 and p53 control proper timing of centrosome separation. Nat Cell Biol 16:538–549. https://doi.org/10.1038/ncb2952
Nguyen HG, Makitalo M, Yang D, Chinnappan D, St Hilaire C, Ravid K (2009) Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J 23:2741–2748. https://doi.org/10.1096/fj.09-130963
Nicholson JM, Cimini D (2013) Cancer karyotypes: survival of the fittest. Front Oncol 3:148. https://doi.org/10.3389/fonc.2013.00148
Orr B, De Sousa F, Gomes AM, Afonso O, Ferreira LT, Figueiredo AC, Maiato H (2021) An anaphase surveillance mechanism prevents micronuclei formation from frequent chromosome segregation errors. Cell Rep 37:109783. https://doi.org/10.1016/j.celrep.2021.109783
Orr B, Talje L, Liu Z, Kwok BH, Compton DA (2016) Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells. Cell Rep 17:1755–1763. https://doi.org/10.1016/j.celrep.2016.10.030
Pampalona J, Roscioli E, Silkworth WT, Bowden B, Genesca A, Tusell L, Cimini D (2016) Chromosome Bridges Maintain Kinetochore-Microtubule Attachment throughout Mitosis and Rarely Break during Anaphase. PLoS One 11:e0147420. https://doi.org/10.1371/journal.pone.0147420
Papini D, Levasseur MD, Higgins JMG (2021) The Aurora B gradient sustains kinetochore stability in anaphase. Cell Rep 37:109818. https://doi.org/10.1016/j.celrep.2021.109818
Paul R, Wollman R, Silkworth WT, Nardi IK, Cimini D, Mogilner A (2009) Computer simulations predict that chromosome movements and rotations accelerate mitotic spindle assembly without compromising accuracy. Proc Natl Acad Sci U S A 106:15708–15713. https://doi.org/10.1073/pnas.0908261106
Perera D, Venkitaraman AR (2016) Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents. Sci Rep 6:29741. https://doi.org/10.1038/srep29741
Pidoux AL, Uzawa S, Perry PE, Cande WZ, Allshire RC (2000) Live analysis of lagging chromosomes during anaphase and their effect on spindle elongation rate in fission yeast. J Cell Sci 113(Pt 23):4177–4191. https://doi.org/10.1242/jcs.113.23.4177
Pincu M, Callisen H, Norman A (1985) DNA content of micronuclei in human lymphocytes. Int J Radiat Biol Relat Stud Phys Chem Med 47:423–432
Rajagopalan H, Lengauer C (2004) Aneuploidy and cancer. Nature 432:338–341. https://doi.org/10.1038/nature03099
Rieder CL, Cole RW, Khodjakov A, Sluder G (1995) 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. https://doi.org/10.1083/jcb.130.4.941
Rieder CL, Schultz A, Cole R, Sluder G (1994) Anaphase onset in vertebrate somatic cells is controlled by a checkpoint that monitors sister kinetochore attachment to the spindle. J Cell Biol 127:1301–1310. https://doi.org/10.1083/jcb.127.5.1301
Rizzoni M, Tanzarella C, Gustavino B, Degrassi F, Guarino A, Vitagliano E (1989) Indirect mitotic nondisjunction in Vicia faba and Chinese hamster cells. Chromosoma 97:339–346. https://doi.org/10.1007/BF00371976
Rizzotto D, Englmaier L, Villunger A (2021) At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity. Int J Mol Sci 2210.3390/ijms221910883
Rumpf C, Cipak L, Schleiffer A, Pidoux A, Mechtler K, Tolic-Norrelykke IM, Gregan J (2010) Laser microsurgery provides evidence for merotelic kinetochore attachments in fission yeast cells lacking Pcs1 or Clr4. Cell Cycle 9:3997–4004. https://doi.org/10.4161/cc.9.19.13233
Sarangapani KK, Asbury CL (2014) Catch and release: how do kinetochores hook the right microtubules during mitosis? Trends Genet 30:150–159. https://doi.org/10.1016/j.tig.2014.02.004
Schuler M, Rupa DS, Eastmond DA (1997) A critical evaluation of centromeric labeling to distinguish micronuclei induced by chromosomal loss and breakage in vitro. Mutat Res 392:81–95. https://doi.org/10.1016/s0165-1218(97)00047-5
Sen O, Harrison JU, Burroughs NJ, McAinsh AD (2021) Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase. Dev Cell 56:3082-3099 e3085. https://doi.org/10.1016/j.devcel.2021.10.007
Shomper M, Lappa C, FitzHarris G (2014) Kinetochore microtubule establishment is defective in oocytes from aged mice. Cell Cycle 13:1171–1179. https://doi.org/10.4161/cc.28046
Silkworth WT, Cimini D (2012) Transient defects of mitotic spindle geometry and chromosome segregation errors. Cell Div 7:19. https://doi.org/10.1186/1747-1028-7-19
Silkworth WT, Nardi IK, Paul R, Mogilner A, Cimini D (2012) Timing of centrosome separation is important for accurate chromosome segregation. Mol Biol Cell 23:401–411. https://doi.org/10.1091/mbc.E11-02-0095
Silkworth WT, Nardi IK, Scholl LM, Cimini D (2009) Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLoS One 4:e6564. https://doi.org/10.1371/journal.pone.0006564
Sluder G, Thompson EA, Miller FJ, Hayes J, Rieder CL (1997) The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry. J Cell Sci 110(Pt 4):421–429. https://doi.org/10.1242/jcs.110.4.421
Soto M, Garcia-Santisteban I, Krenning L, Medema RH, Raaijmakers JA (2018) Chromosomes trapped in micronuclei are liable to segregation errors. J Cell Sci 13110.1242/jcs.214742
Stear JH, Roth MB (2002) Characterization of HCP-6, a C. elegans protein required to prevent chromosome twisting and merotelic attachment. Genes Dev 16:1498–1508. https://doi.org/10.1101/gad.989102
Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40. https://doi.org/10.1016/j.cell.2010.11.055
Stewenius Y, Jin Y, Ora I, de Kraker J, Bras J, Frigyesi A, Alumets J, Sandstedt B, Meeker AK, Gisselsson D (2007) Defective chromosome segregation and telomere dysfunction in aggressive Wilms’ tumors. Clin Cancer Res 13:6593–6602. https://doi.org/10.1158/1078-0432.CCR-07-1081
Streffer C, van Beuningen D, Rebmann A (1985) DNA measurements and micronuclei in human rectal carcinoma. Radiat Med 3:147–150
Tanaka TU, Rachidi N, Janke C, Pereira G, Galova M, Schiebel E, Stark MJ, Nasmyth K (2002) Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108:317–329. https://doi.org/10.1016/s0092-8674(02)00633-5
Terradas M, Martin M, Hernandez L, Tusell L, Genesca A (2012) Nuclear envelope defects impede a proper response to micronuclear DNA lesions. Mutat Res 729:35–40. https://doi.org/10.1016/j.mrfmmm.2011.09.003
Terradas M, Martin M, Tusell L, Genesca A (2009) DNA lesions sequestered in micronuclei induce a local defective-damage response. DNA Repair (amst) 8:1225–1234. https://doi.org/10.1016/j.dnarep.2009.07.004
Thompson SL, Compton DA (2008) Examining the link between chromosomal instability and aneuploidy in human cells. J Cell Biol 180:665–672. https://doi.org/10.1083/jcb.200712029
Thompson SL, Compton DA (2011) Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. Proc Natl Acad Sci U S A 108:17974–17978. https://doi.org/10.1073/pnas.1109720108
Thomson EJ, Perry PE (1988) The identification of micronucleated chromosomes: a possible assay for aneuploidy. Mutagenesis 3:415–418. https://doi.org/10.1093/mutage/3.5.415
Trivedi P, Zaytsev AV, Godzi M, Ataullakhanov FI, Grishchuk EL, Stukenberg PT (2019) The binding of Borealin to microtubules underlies a tension independent kinetochore-microtubule error correction pathway. Nat Commun 10:682. https://doi.org/10.1038/s41467-019-08418-4
Tucker JB, Bonema SC, Garcia-Varela R, Denu RA, Hu Y, McGregor SM, Burkard ME, Weaver BA (2023) Misaligned Chromosomes are a Major Source of Chromosomal Instability in Breast Cancer. Cancer Res Commun 3:54–65. https://doi.org/10.1158/2767-9764.CRC-22-0302
Umbreit NT, Zhang CZ, Lynch LD, Blaine LJ, Cheng AM, Tourdot R, Sun L, Almubarak HF, Judge K, Mitchell TJ, Spektor A, Pellman D (2020) Mechanisms generating cancer genome complexity from a single cell division error. Science 368. https://doi.org/10.1126/science.aba0712
Vazquez-Diez C, Yamagata K, Trivedi S, Haverfield J, FitzHarris G (2016) Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos. Proc Natl Acad Sci U S A 113:626–631. https://doi.org/10.1073/pnas.1517628112
Venkatesan S, Angelova M, Puttick C, Zhai H, Caswell DR, Lu WT, Dietzen M, Galanos P, Evangelou K, Bellelli R, Lim EL, Watkins TBK, Rowan A, Teixeira VH, Zhao Y, Chen H, Ngo B, Zalmas LP, Al Bakir M, Hobor S, Gronroos E, Pennycuick A, Nigro E, Campbell BB, Brown WL, Akarca AU, Marafioti T, Wu MY, Howell M, Boulton SJ, Bertoli C, Fenton TR, de Bruin RAM, Maya-Mendoza A, Santoni-Rugiu E, Hynds RE, Gorgoulis VG, Jamal-Hanjani M, McGranahan N, Harris RS, Janes SM, Bartkova J, Bakhoum SF, Bartek J, Kanu N, Swanton C, Consortium TR (2021) Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution. Cancer Discov 11:2456–2473. https://doi.org/10.1158/2159-8290.CD-20-0725
Weaver BA, Cleveland DW (2006) Does aneuploidy cause cancer? Curr Opin Cell Biol 18:658–667. https://doi.org/10.1016/j.ceb.2006.10.002
Wise DA, Brinkley BR (1997) Mitosis in cells with unreplicated genomes (MUGs): spindle assembly and behavior of centromere fragments. Cell Motil Cytoskeleton 36:291–302. https://doi.org/10.1002/(SICI)1097-0169(1997)36:3%3c291::AID-CM9%3e3.0.CO;2-A
Worrall JT, Tamura N, Mazzagatti A, Shaikh N, van Lingen T, Bakker B, Spierings DCJ, Vladimirou E, Foijer F, McClelland SE (2018) Non-random Mis-segregation of Human Chromosomes. Cell Rep 23:3366–3380. https://doi.org/10.1016/j.celrep.2018.05.047
Yamamoto KI, Kikuchi Y (1980) A comparison of diameters of micronuclei induced by clastogens and by spindle poisons. Mutat Res 71:127–131. https://doi.org/10.1016/0027-5107(80)90012-3
Yu HG, Dawe RK (2000) Functional redundancy in the maize meiotic kinetochore. J Cell Biol 151:131–142. https://doi.org/10.1083/jcb.151.1.131
Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, Lawrence MS, Zhsng CZ, Wala J, Mermel CH, Sougnez C, Gabriel SB, Hernandez B, Shen H, Laird PW, Getz G, Meyerson M, Beroukhim R (2013) Pan-cancer patterns of somatic copy number alteration. Nat Genet 45:1134–1140. https://doi.org/10.1038/ng.2760
Zaki BI, Suriawinata AA, Eastman AR, Garner KM, Bakhoum SF (2014) Chromosomal instability portends superior response of rectal adenocarcinoma to chemoradiation therapy. Cancer 120:1733–1742. https://doi.org/10.1002/cncr.28656
Zerbib J, Ippolito MR, Eliezer Y, De Feudis G, Reuveni E, Kadmon AS, Martin S, Viganò S, Leor G, Berstler J, Laue K, Cohen-Sharir Y, Scorzoni S, Vazquez F, Ben-David U, Santaguida S (2023) Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage. bioRxiv
Zhai Y, Kronebusch PJ, Borisy GG (1995) Kinetochore microtubule dynamics and the metaphase-anaphase transition. J Cell Biol 131:721–734. https://doi.org/10.1083/jcb.131.3.721
Zhang CZ, Spektor A, Cornils H, Francis JM, Jackson EK, Liu S, Meyerson M, Pellman D (2015) Chromothripsis from DNA damage in micronuclei. Nature 522:179–184. https://doi.org/10.1038/nature14493
Zhang X, Lan W, Ems-McClung SC, Stukenberg PT, Walczak CE (2007) Aurora B phosphorylates multiple sites on mitotic centromere-associated kinesin to spatially and temporally regulate its function. Mol Biol Cell 18:3264–3276. https://doi.org/10.1091/mbc.e07-01-0086
Zielinska AP, Holubcova Z, Blayney M, Elder K, Schuh M (2015) Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect. Elife 4:e11389. https://doi.org/10.7554/eLife.11389
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I would like to acknowledge all members of the Cimini lab for helpful discussions and careful reading of the manuscript.
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Work in the Cimini lab is supported by grant #R01GM140042 from the U.S. National Institutes of Health. Additional funding is provided by a Dean’s Discovery Fund award to DC from the Virginia Tech College of Science.
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Cimini, D. Twenty years of merotelic kinetochore attachments: a historical perspective. Chromosome Res 31, 18 (2023). https://doi.org/10.1007/s10577-023-09727-7
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DOI: https://doi.org/10.1007/s10577-023-09727-7