Home LiteratureArticle Details
PMID: 15359281 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Centrosome amplification induced by DNA damage occurs during a prolonged G2 phase and involves ATM.

The EMBO journal ·Vol. 23 ·No. 19 ·2004-10-01 ·Pages 3864-73

Dodson H, Bourke E, Jeffers LJ, Vagnarelli P, Sonoda E, Takeda S, Earnshaw WC, Merdes A, Morrison C

Abstract

Centrosomes are the principal microtubule organising centres in somatic cells. Abnormal centrosome number is common in tumours and occurs after gamma-irradiation and in cells with mutations in DNA repair genes. To investigate how DNA damage causes centrosome amplification, we examined cells that conditionally lack the Rad51 recombinase and thereby incur high levels of spontaneous DNA damage. Rad51-deficient cells arrested in G2 phase and formed supernumerary functional centrosomes, as assessed by light and serial section electron microscopy. This centrosome amplification occurred without an additional DNA replication round and was not the result of cytokinesis failure. G2-to-M checkpoint over-ride by caffeine or wortmannin treatment strongly reduced DNA damage-induced centrosome amplification. Radiation-induced centrosome amplification was potentiated by Rad54 disruption. Gene targeting of ATM reduced, but did not abrogate, centrosome amplification induced by DNA damage in both the Rad51 and Rad54 knockout models, demonstrating ATM-dependent and -independent components of DNA damage-inducible G2-phase centrosome amplification. Our data suggest DNA damage-induced centrosome amplification as a mechanism for ensuring death of cells that evade the DNA damage or spindle assembly checkpoints.

MeSH Terms
Androstadienes/pharmacology Animals Ataxia Telangiectasia Mutated Proteins Avian Proteins Caffeine/pharmacology Cell Cycle Proteins/genetics,physiology Cell Division Central Nervous System Stimulants/pharmacology Centrosome/physiology Chickens Chromosomal Instability Cytokinesis DNA Damage DNA Helicases DNA Replication DNA-Binding Proteins/genetics,physiology G2 Phase Gene Amplification Gene Targeting Humans Laser Scanning Cytometry Mice Mitosis Mycotoxins/pharmacology Nuclear Proteins/genetics,physiology Protein Kinase Inhibitors/pharmacology Protein Serine-Threonine Kinases/genetics,physiology Rad51 Recombinase Tumor Suppressor Proteins/genetics,physiology Wortmannin
Chemicals
Androstadienes Avian Proteins Cell Cycle Proteins Central Nervous System Stimulants DNA-Binding Proteins Mycotoxins Nuclear Proteins Protein Kinase Inhibitors Tumor Suppressor Proteins Caffeine ATM protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases RAD51 protein, Gallus gallus RAD51 protein, human Rad51 Recombinase Rad51 protein, mouse DNA Helicases RAD54L protein, human Wortmannin
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Dodson Helen
Department of Biochemistry and NCBES, National University of Ireland-Galway, Galway, Ireland.
Bourke Emer
Jeffers Liam J
Vagnarelli Paola
Sonoda Eiichiro
Takeda Shunichi
Earnshaw William C
Merdes Andreas
Morrison Ciaran
References (56)
56 references, click to expand
  1. Caffeine inhibits the checkpoint kinase ATM.
    Curr Biol. 1999 Oct 7;9(19):1135-8 PMID: 10531013
  2. Re-evaluating centrosome function.
    Nat Rev Mol Cell Biol. 2001 Sep;2(9):688-98 PMID: 11533726
  3. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification.
    Curr Biol. 1999 Oct 7;9(19):1107-10 PMID: 10531007
  4. Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells.
    EMBO J. 1999 Dec 1;18(23):6619-29 PMID: 10581236
  5. Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation.
    Oncogene. 1999 Nov 25;18(50):7002-9 PMID: 10597300
  6. Centrioles reveal their secrets.
    Nat Cell Biol. 1999 Jul;1(3):E62-4 PMID: 10559911
  7. The controlling role of ATM in homologous recombinational repair of DNA damage.
    EMBO J. 2000 Feb 1;19(3):463-71 PMID: 10654944
  8. Purification and characterization of ATM from human placenta. A manganese-dependent, wortmannin-sensitive serine/threonine protein kinase.
    J Biol Chem. 2000 Mar 17;275(11):7803-10 PMID: 10713094
  9. Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity.
    J Biol Chem. 2000 Apr 7;275(14):10342-8 PMID: 10744722
  10. The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells.
    J Cell Biol. 2000 Apr 17;149(2):317-30 PMID: 10769025
  11. GFP-centrin as a marker for centriole dynamics in living cells.
    Microsc Res Tech. 2000 Jun 1;49(5):451-7 PMID: 10842372
  12. The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle.
    Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10002-7 PMID: 10944189
  13. Cell cycle checkpoint signaling through the ATM and ATR kinases.
    Genes Dev. 2001 Sep 1;15(17):2177-96 PMID: 11544175
  14. Centrosome reproduction in Xenopus lysates.
    Methods Cell Biol. 2001;67:269-87 PMID: 11550474
  15. Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells.
    Dev Cell. 2001 Dec;1(6):759-70 PMID: 11740938
  16. Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions.
    Mol Cell Biol. 2002 Jan;22(2):669-79 PMID: 11756561
  17. Integration of the centrosome in cell cycle control, stress response and signal transduction pathways.
    Curr Opin Cell Biol. 2002 Feb;14(1):35-43 PMID: 11792542
  18. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53-/- cells.
    EMBO J. 2002 Feb 15;21(4):483-92 PMID: 11847097
  19. Centrosome amplification and the development of cancer.
    Oncogene. 2002 Sep 9;21(40):6146-53 PMID: 12214243
  20. Loss of p53 and centrosome hyperamplification.
    Oncogene. 2002 Sep 9;21(40):6234-40 PMID: 12214254
  21. ATM and related protein kinases: safeguarding genome integrity.
    Nat Rev Cancer. 2003 Mar;3(3):155-68 PMID: 12612651
  22. Involvement of poly(ADP-Ribose) polymerase 1 and poly(ADP-Ribosyl)ation in regulation of centrosome function.
    Mol Cell Biol. 2003 Apr;23(7):2451-62 PMID: 12640128
  23. Drosophila checkpoint kinase 2 couples centrosome function and spindle assembly to genomic integrity.
    Cell. 2003 Apr 4;113(1):87-99 PMID: 12679037
  24. Centrosome number is controlled by a centrosome-intrinsic block to reduplication.
    Nat Cell Biol. 2003 Jun;5(6):539-44 PMID: 12766773
  25. Centrosomes split in the presence of impaired DNA integrity during mitosis.
    Mol Biol Cell. 2003 May;14(5):1993-2004 PMID: 12802070
  26. Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases.
    J Biol Chem. 2003 Sep 26;278(39):37139-45 PMID: 12847089
  27. Overexpression of mammalian Rad51 does not stimulate tumorigenesis while a dominant-negative Rad51 affects centrosome fragmentation, ploidy and stimulates tumorigenesis, in p53-defective CHO cells.
    Oncogene. 2003 Oct 23;22(48):7587-92 PMID: 14576820
  28. Caffeine and human DNA metabolism: the magic and the mystery.
    Mutat Res. 2003 Nov 27;532(1-2):85-102 PMID: 14643431
  29. The good, the bad and the ugly: the practical consequences of centrosome amplification.
    Curr Opin Cell Biol. 2004 Feb;16(1):49-54 PMID: 15037304
  30. The cell cycle checkpoint kinase Chk2 is a negative regulator of mitotic catastrophe.
    Oncogene. 2004 May 27;23(25):4353-61 PMID: 15048074
  31. Mechanism by which caffeine potentiates lethality of nitrogen mustard.
    Proc Natl Acad Sci U S A. 1982 May;79(9):2942-6 PMID: 6953438
  32. Centrioles in the cell cycle. I. Epithelial cells.
    J Cell Biol. 1982 Jun;93(3):938-49 PMID: 7119006
  33. Microtubule-organizing centers abnormal in number, structure, and nucleating activity in x-irradiated mammalian cells.
    J Cell Biol. 1983 Mar;96(3):776-82 PMID: 6833383
  34. Control mechanisms of the cell cycle: role of the spatial arrangement of spindle components in the timing of mitotic events.
    J Cell Biol. 1983 Sep;97(3):877-86 PMID: 6885924
  35. Centriole distribution during tripolar mitosis in Chinese hamster ovary cells.
    J Cell Biol. 1984 Jun;98(6):2222-9 PMID: 6373793
  36. Relationship between nuclear DNA synthesis and centrosome reproduction in sea urchin eggs.
    J Exp Zool. 1987 Oct;244(1):89-100 PMID: 3694143
  37. Nuclear and cytoplasmic mitotic cycles continue in Drosophila embryos in which DNA synthesis is inhibited with aphidicolin.
    J Cell Biol. 1988 Dec;107(6 Pt 1):2009-19 PMID: 3143733
  38. Protein synthesis and the cell cycle: centrosome reproduction in sea urchin eggs is not under translational control.
    J Cell Biol. 1990 Jun;110(6):2025-32 PMID: 2351692
  39. Centrosome duplication continues in cycloheximide-treated Xenopus blastulae in the absence of a detectable cell cycle.
    J Cell Biol. 1990 Jun;110(6):2033-42 PMID: 2190990
  40. Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells.
    J Cell Biol. 1995 Jul;130(1):105-15 PMID: 7790366
  41. Abnormal centrosome amplification in the absence of p53.
    Science. 1996 Mar 22;271(5256):1744-7 PMID: 8596939
  42. Most of centrin in animal cells is not centrosome-associated and centrosomal centrin is confined to the distal lumen of centrioles.
    J Cell Sci. 1996 Dec;109 ( Pt 13):3089-102 PMID: 9004043
  43. Reduced X-ray resistance and homologous recombination frequencies in a RAD54-/- mutant of the chicken DT40 cell line.
    Cell. 1997 Apr 18;89(2):185-93 PMID: 9108474
  44. Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death.
    EMBO J. 1998 Jan 15;17(2):598-608 PMID: 9430650
  45. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity.
    Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2950-5 PMID: 9501196
  46. Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin.
    Cancer Res. 1998 Oct 1;58(19):4375-82 PMID: 9766667
  47. Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts.
    Science. 1999 Feb 5;283(5403):851-4 PMID: 9933170
  48. Cyclin-dependent kinase control of centrosome duplication.
    Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2817-22 PMID: 10077594
  49. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.
    Mol Cell. 1999 Mar;3(3):389-95 PMID: 10198641
  50. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
    Cancer Res. 1999 Sep 1;59(17):4375-82 PMID: 10485486
  51. Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation.
    Nat Cell Biol. 2000 Oct;2(10):757-61 PMID: 11025669
  52. A possible role for centrosome overduplication in radiation-induced cell death.
    Oncogene. 2000 Nov 2;19(46):5281-90 PMID: 11077445
  53. Managing the centrosome numbers game: from chaos to stability in cancer cell division.
    Trends Cell Biol. 2001 Jan;11(1):18-21 PMID: 11146294
  54. Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression.
    Cancer Res. 2001 Mar 1;61(5):2212-9 PMID: 11280789
  55. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1.
    Mol Biol Cell. 2001 May;12(5):1315-28 PMID: 11359924
  56. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A.
    Nat Cell Biol. 1999 Jun;1(2):88-93 PMID: 10559879
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600393
Published
2004-10-01
Epub
2004-00-09
Pages
3864-73
Language
English
Region
England
NLM ID
8208664
PMCID
PMC522792
Subset
IM
Grants
Wellcome Trust · 073915 · United Kingdom
External Links
PubMed source DOI: 10.1038/sj.emboj.7600393 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2