Too Much to Handle - How Gaining Chromosomes Destabilizes the Genome

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2016 Sep 17

PMID 27636196

Citations 5

Authors

Verena Passerini

Zuzana Storchova

Affiliations

Soon will be listed here.

Abstract

Most eukaryotic organisms are diploid, with 2 chromosome sets in their nuclei. Whole chromosomal aneuploidy, a deviation from multiples of the haploid chromosome number, arises from chromosome segregation errors and often has detrimental consequences for cells. In humans, numerical aneuploidy severely impairs embryonic development and the rare survivors develop disorders characterized by multiple pathologies. Moreover, as many as 75 % of malignant tumors display aneuploidy. Although the exact contribution of aneuploidy to tumorigenesis remains unclear, previous studies have suggested that aneuploidy may affect the maintenance of genome integrity. We found that human cells with extra chromosomes showed phenotypes suggestive of replication defects, a phenomenon which we went on to characterize as being due to the aneuploidy-driven downregulation of replication factors, in particular of the replicative helicase MCM2-7. Thus, missegregation of even a single chromosome can further promote genomic instability and thereby contribute to tumor development. In this review we will examine the possible causes of downregulation of replicative factors and discuss the consequences of genomic instability in aneuploid cells.

Citing Articles

Profiling chromosomal-level variations in gastric malignancies.

Negoto T, Jo M, Nakayama I, Morioka M, Takeuchi K, Kawachi H Cancer Sci. 2022; 113(11):3864-3876.

PMID: 36002148 PMC: 9633305. DOI: 10.1111/cas.15544.

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice.

Schukken K, Zhu Y, Bakker P, Koster M, Harkema L, Youssef S Sci Rep. 2021; 11(1):68.

PMID: 33420244 PMC: 7794249. DOI: 10.1038/s41598-020-80169-5.

Exploiting aneuploidy-imposed stresses and coping mechanisms to battle cancer.

Zhou L, Jilderda L, Foijer F Open Biol. 2020; 10(9):200148.

PMID: 32873156 PMC: 7536071. DOI: 10.1098/rsob.200148.

Investigating the Vinblastine Induced-Chromosomal Abnormality in the Already Gamma Irradiated L929 Cell Line Using Micronucleus Assay in Cytokinesis Blocked Binucleated Cells.

Mohammadi Z, Haddad F, Matin M, Soleymanifard S Asian Pac J Cancer Prev. 2019; 20(4):1045-1050.

PMID: 31030472 PMC: 6948891. DOI: 10.31557/APJCP.2019.20.4.1045.

The plasmid-borne quinolone resistance protein QnrB, a novel DnaA-binding protein, increases the bacterial mutation rate by triggering DNA replication stress.

Li X, Zhang Y, Zhou X, Hu X, Zhou Y, Liu D Mol Microbiol. 2019; 111(6):1529-1543.

PMID: 30838726 PMC: 6617969. DOI: 10.1111/mmi.14235.

References

Williams B, Prabhu V, Hunter K, Glazier C, Whittaker C, Housman D . Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008; 322(5902):703-9. PMC: 2701511. DOI: 10.1126/science.1160058. View

Yona A, Manor Y, Herbst R, Romano G, Mitchell A, Kupiec M . Chromosomal duplication is a transient evolutionary solution to stress. Proc Natl Acad Sci U S A. 2012; 109(51):21010-5. PMC: 3529009. DOI: 10.1073/pnas.1211150109. View

Chuang C, Yang D, Bai G, Freeland A, Pruitt S, Schimenti J . Post-transcriptional homeostasis and regulation of MCM2-7 in mammalian cells. Nucleic Acids Res. 2012; 40(11):4914-24. PMC: 3367205. DOI: 10.1093/nar/gks176. View

Rutledge S, Douglas T, Nicholson J, Vila-Casadesus M, Kantzler C, Wangsa D . Selective advantage of trisomic human cells cultured in non-standard conditions. Sci Rep. 2016; 6:22828. PMC: 4783771. DOI: 10.1038/srep22828. View

Gorgoulis V, Vassiliou L, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T . Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature. 2005; 434(7035):907-13. DOI: 10.1038/nature03485. View

Ibarra A, Schwob E, Mendez J . Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc Natl Acad Sci U S A. 2008; 105(26):8956-61. PMC: 2449346. DOI: 10.1073/pnas.0803978105. View

Flach J, Bakker S, Mohrin M, Conroy P, Pietras E, Reynaud D . Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature. 2014; 512(7513):198-202. PMC: 4456040. DOI: 10.1038/nature13619. View

Oromendia A, Dodgson S, Amon A . Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 2012; 26(24):2696-708. PMC: 3533075. DOI: 10.1101/gad.207407.112. View

Hughes C, Guasti L, Meimaridou E, Chuang C, Schimenti J, King P . MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012; 122(3):814-20. PMC: 3287227. DOI: 10.1172/JCI60224. View

10.

Necchi D, Pinto A, Tillhon M, Dutto I, Serafini M, Lanni C . Defective DNA repair and increased chromatin binding of DNA repair factors in Down syndrome fibroblasts. Mutat Res. 2015; 780:15-23. DOI: 10.1016/j.mrfmmm.2015.07.009. View

11.

Sheltzer J, Torres E, Dunham M, Amon A . Transcriptional consequences of aneuploidy. Proc Natl Acad Sci U S A. 2012; 109(31):12644-9. PMC: 3411958. DOI: 10.1073/pnas.1209227109. View

12.

Kawabata T, Yamaguchi S, Buske T, Luebben S, Wallace M, Matise I . A reduction of licensed origins reveals strain-specific replication dynamics in mice. Mamm Genome. 2011; 22(9-10):506-17. PMC: 3528403. DOI: 10.1007/s00335-011-9333-7. View

13.

Hanks S, Coleman K, Reid S, Plaja A, Firth H, Fitzpatrick D . Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat Genet. 2004; 36(11):1159-61. DOI: 10.1038/ng1449. View

14.

Woodward A, Gohler T, Luciani M, Oehlmann M, Ge X, Gartner A . Excess Mcm2-7 license dormant origins of replication that can be used under conditions of replicative stress. J Cell Biol. 2006; 173(5):673-83. PMC: 2063885. DOI: 10.1083/jcb.200602108. View

15.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

16.

Morawiec Z, Janik K, Kowalski M, Stetkiewicz T, Szaflik J, Morawiec-Bajda A . DNA damage and repair in children with Down's syndrome. Mutat Res. 2007; 637(1-2):118-23. DOI: 10.1016/j.mrfmmm.2007.07.010. View

17.

Alvarez S, Diaz M, Flach J, Rodriguez-Acebes S, Lopez-Contreras A, Martinez D . Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality. Nat Commun. 2015; 6:8548. PMC: 4608254. DOI: 10.1038/ncomms9548. View

18.

Durrbaum M, Kuznetsova A, Passerini V, Stingele S, Stoehr G, Storchova Z . Unique features of the transcriptional response to model aneuploidy in human cells. BMC Genomics. 2014; 15:139. PMC: 3932016. DOI: 10.1186/1471-2164-15-139. View

19.

Ganmore I, Smooha G, Izraeli S . Constitutional aneuploidy and cancer predisposition. Hum Mol Genet. 2009; 18(R1):R84-93. PMC: 2657942. DOI: 10.1093/hmg/ddp084. View

20.

Sotillo R, Schvartzman J, Socci N, Benezra R . Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature. 2010; 464(7287):436-40. PMC: 2841716. DOI: 10.1038/nature08803. View