Mitotic Entry in the Presence of DNA Damage is a Widespread Property of Aneuploidy in Yeast

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2015 Feb 20

PMID 25694455

Citations 26

Authors

Heidi M Blank

Jason M Sheltzer

Colleen M Meehl

Angelika Amon

Affiliations

Soon will be listed here.

Abstract

Genetic instability is a hallmark of aneuploidy in budding and fission yeast. All aneuploid yeast strains analyzed to date harbor elevated levels of Rad52-GFP foci, a sign of DNA damage. Here we investigate how continuously elevated levels of DNA damage affect aneuploid cells. We show that Rad52-GFP foci form during S phase, consistent with the observation that DNA replication initiation and elongation are impaired in some aneuploid yeast strains. We furthermore find that although DNA damage is low in aneuploid cells, it nevertheless has dramatic consequences. Many aneuploid yeast strains adapt to DNA damage and undergo mitosis despite the presence of unrepaired DNA leading to cell death. Wild-type cells exposed to low levels of DNA damage exhibit a similar phenotype, indicating that adaptation to low levels of unrepaired DNA is a general property of the cell's response to DNA damage. Our results indicate that by causing low levels of DNA damage, whole-chromosome aneuploidies lead to DNA breaks that persist into mitosis. Such breaks provide the substrate for translocations and deletions that are a hallmark of cancer.

Citing Articles

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References

Lisby M, Rothstein R, Mortensen U . Rad52 forms DNA repair and recombination centers during S phase. Proc Natl Acad Sci U S A. 2001; 98(15):8276-82. PMC: 37432. DOI: 10.1073/pnas.121006298. View

Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W . DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature. 2004; 431(7011):1011-7. PMC: 4493751. DOI: 10.1038/nature02964. View

Yoo H, Kumagai A, Shevchenko A, Shevchenko A, Dunphy W . Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell. 2004; 117(5):575-88. DOI: 10.1016/s0092-8674(04)00417-9. 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

Zhang Y, Yu Z, Fu X, Liang C . Noc3p, a bHLH protein, plays an integral role in the initiation of DNA replication in budding yeast. Cell. 2002; 109(7):849-60. DOI: 10.1016/s0092-8674(02)00805-x. View

Stracker T, Petrini J . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011; 12(2):90-103. PMC: 3905242. DOI: 10.1038/nrm3047. View

Niwa O, Tange Y, Kurabayashi A . Growth arrest and chromosome instability in aneuploid yeast. Yeast. 2006; 23(13):937-50. DOI: 10.1002/yea.1411. View

Zhu J, Pavelka N, Bradford W, Rancati G, Li R . Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet. 2012; 8(5):e1002719. PMC: 3355078. DOI: 10.1371/journal.pgen.1002719. View

Yabuki N, Terashima H, Kitada K . Mapping of early firing origins on a replication profile of budding yeast. Genes Cells. 2002; 7(8):781-9. DOI: 10.1046/j.1365-2443.2002.00559.x. View

10.

Yoshida K, Bacal J, Desmarais D, Padioleau I, Tsaponina O, Chabes A . The histone deacetylases sir2 and rpd3 act on ribosomal DNA to control the replication program in budding yeast. Mol Cell. 2014; 54(4):691-7. DOI: 10.1016/j.molcel.2014.04.032. View

11.

Sheltzer J, Amon A . The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet. 2011; 27(11):446-53. PMC: 3197822. DOI: 10.1016/j.tig.2011.07.003. View

12.

Hodgson B, Calzada A, Labib K . Mrc1 and Tof1 regulate DNA replication forks in different ways during normal S phase. Mol Biol Cell. 2007; 18(10):3894-902. PMC: 1995724. DOI: 10.1091/mbc.e07-05-0500. View

13.

Torres E, Dephoure N, Panneerselvam A, Tucker C, Whittaker C, Gygi S . Identification of aneuploidy-tolerating mutations. Cell. 2010; 143(1):71-83. PMC: 2993244. DOI: 10.1016/j.cell.2010.08.038. View

14.

Li M, Fang X, Wei Z, York J, Zhang P . Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. J Cell Biol. 2009; 185(6):983-94. PMC: 2711613. DOI: 10.1083/jcb.200904020. View

15.

Epstein C, Cross F . CLB5: a novel B cyclin from budding yeast with a role in S phase. Genes Dev. 1992; 6(9):1695-706. DOI: 10.1101/gad.6.9.1695. View

16.

Dephoure N, Hwang S, OSullivan C, Dodgson S, Gygi S, Amon A . Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. Elife. 2014; 3:e03023. PMC: 4129440. DOI: 10.7554/eLife.03023. View

17.

Serrano D, DAmours D . When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage. Syst Synth Biol. 2014; 8(3):195-203. PMC: 4127177. DOI: 10.1007/s11693-014-9151-9. View

18.

Gasch A, Spellman P, Kao C, Eisen M, Storz G, Botstein D . Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell. 2000; 11(12):4241-57. PMC: 15070. DOI: 10.1091/mbc.11.12.4241. View

19.

Toczyski D, Galgoczy D, Hartwell L . CDC5 and CKII control adaptation to the yeast DNA damage checkpoint. Cell. 1997; 90(6):1097-106. DOI: 10.1016/s0092-8674(00)80375-x. View

20.

Blitzblau H, Chan C, Hochwagen A, Bell S . Separation of DNA replication from the assembly of break-competent meiotic chromosomes. PLoS Genet. 2012; 8(5):e1002643. PMC: 3355065. DOI: 10.1371/journal.pgen.1002643. View