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PMID: 22258507 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

DNA breaks and chromosome pulverization from errors in mitosis.

Nature ·Vol. 482 ·No. 7383 ·2012-01-18 ·Pages 53-8

Crasta K, Ganem NJ, Dagher R, Lantermann AB, Ivanova EV, Pan Y, Nezi L, Protopopov A, Chowdhury D, Pellman D

Abstract

The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.

MeSH Terms
Aneuploidy Cell Line, Tumor Cell Transformation, Neoplastic/genetics,pathology Chromosome Breakage Chromosome Segregation Comet Assay DNA Fragmentation DNA Replication Humans Micronuclei, Chromosome-Defective Mitosis/genetics Neoplasms/etiology,genetics,pathology
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Crasta Karen
Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA.
Ganem Neil J
Dagher Regina
Lantermann Alexandra B
Ivanova Elena V
Pan Yunfeng
Nezi Luigi
Protopopov Alexei
Chowdhury Dipanjan
Pellman David
References (49)
49 references, click to expand
  1. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation.
    J Cell Biol. 1992 Nov;119(3):493-501 PMID: 1400587
  2. Replication protein A phosphorylation and the cellular response to DNA damage.
    DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1015-24 PMID: 15279788
  3. A mechanism linking extra centrosomes to chromosomal instability.
    Nature. 2009 Jul 9;460(7252):278-82 PMID: 19506557
  4. Causes and consequences of aneuploidy in cancer.
    Nat Rev Genet. 2012 Jan 24;13(3):189-203 PMID: 22269907
  5. Dynamics of pre-replication complex proteins during the cell division cycle.
    Philos Trans R Soc Lond B Biol Sci. 2004 Jan 29;359(1441):7-16 PMID: 15065651
  6. Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction.
    Mol Biol Cell. 2012 Feb;23(4):567-76 PMID: 22171325
  7. Abnormal nuclear shape in solid tumors reflects mitotic instability.
    Am J Pathol. 2001 Jan;158(1):199-206 PMID: 11141493
  8. Delayed replication timing leads to delayed mitotic chromosome condensation and chromosomal instability of chromosome translocations.
    Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13300-5 PMID: 11698686
  9. An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein.
    Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12651-6 PMID: 12271129
  10. Merotelic kinetochore orientation, aneuploidy, and cancer.
    Biochim Biophys Acta. 2008 Sep;1786(1):32-40 PMID: 18549824
  11. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells.
    Nature. 2005 Oct 13;437(7061):1043-7 PMID: 16222300
  12. DNA lesions sequestered in micronuclei induce a local defective-damage response.
    DNA Repair (Amst). 2009 Oct 2;8(10):1225-34 PMID: 19683478
  13. hNuf2 inhibition blocks stable kinetochore-microtubule attachment and induces mitotic cell death in HeLa cells.
    J Cell Biol. 2002 Nov 25;159(4):549-55 PMID: 12438418
  14. Genetic activities in micronuclei: is the DNA entrapped in micronuclei lost for the cell?
    Mutat Res. 2010 Jul-Sep;705(1):60-7 PMID: 20307686
  15. Mismatch repair proteins are activators of toxic responses to chromium-DNA damage.
    Mol Cell Biol. 2005 May;25(9):3596-607 PMID: 15831465
  16. The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis.
    Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14188-93 PMID: 20663956
  17. Aneuploidy acts both oncogenically and as a tumor suppressor.
    Cancer Cell. 2007 Jan;11(1):25-36 PMID: 17189716
  18. Whole chromosome instability and cancer: a complex relationship.
    Trends Genet. 2008 Sep;24(9):457-66 PMID: 18675487
  19. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity.
    Cancer Cell. 2009 Dec 8;16(6):475-86 PMID: 19962666
  20. Sustained mitotic block elicits DNA breaks: one-step alteration of ploidy and chromosome integrity in mammalian cells.
    Oncogene. 2007 Jan 11;26(2):165-72 PMID: 16832348
  21. Chromosome pulverization in human binucleate cells following colcemid treatment.
    J Cell Biol. 1967 Jul;34(1):35-45 PMID: 6033541
  22. Maintaining genome stability at the replication fork.
    Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19 PMID: 20177396
  23. Three-dimensional organization of micronuclei induced by colchicine in PtK1 cells.
    Exp Cell Res. 1989 Mar;181(1):27-39 PMID: 2917606
  24. Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors.
    Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):17974-8 PMID: 21997207
  25. Mammalian cell fusion: induction of premature chromosome condensation in interphase nuclei.
    Nature. 1970 May 23;226(5247):717-22 PMID: 5443247
  26. Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
    Cell. 2011 Jan 7;144(1):27-40 PMID: 21215367
  27. Human cancer cells commonly acquire DNA damage during mitotic arrest.
    Cancer Res. 2007 Dec 15;67(24):11487-92 PMID: 18089775
  28. Aneuploidy: instigator and inhibitor of tumorigenesis.
    Cancer Res. 2007 Nov 1;67(21):10103-5 PMID: 17974949
  29. Mitotic chromosomal instability and cancer: mouse modelling of the human disease.
    Nat Rev Cancer. 2010 Feb;10(2):102-15 PMID: 20094045
  30. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations.
    Science. 2011 Sep 30;333(6051):1895-8 PMID: 21960636
  31. The human leukocyte test system. III. Premature chromosome condensation from chemically and x-ray induced micronuclei.
    Mutat Res. 1975 Jan;27(1):89-101 PMID: 47608
  32. Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks.
    J Cell Biol. 2006 Apr 24;173(2):195-206 PMID: 16618811
  33. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells.
    J Cell Biol. 2001 Apr 30;153(3):517-27 PMID: 11331303
  34. Chromatin association of human origin recognition complex, cdc6, and minichromosome maintenance proteins during the cell cycle: assembly of prereplication complexes in late mitosis.
    Mol Cell Biol. 2000 Nov;20(22):8602-12 PMID: 11046155
  35. Resolution of anaphase bridges in cancer cells.
    Chromosoma. 2004 Jun;112(8):389-97 PMID: 15156327
  36. A simple technique for quantitation of low levels of DNA damage in individual cells.
    Exp Cell Res. 1988 Mar;175(1):184-91 PMID: 3345800
  37. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.
    Cell. 2011 Sep 16;146(6):889-903 PMID: 21925314
  38. Depletion of centromeric MCAK leads to chromosome congression and segregation defects due to improper kinetochore attachments.
    Mol Biol Cell. 2004 Mar;15(3):1146-59 PMID: 14699064
  39. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice.
    Cancer Cell. 2007 Jan;11(1):9-23 PMID: 17189715
  40. Inactivation of a human kinetochore by specific targeting of chromatin modifiers.
    Dev Cell. 2008 Apr;14(4):507-22 PMID: 18410728
  41. Chromosome damage associated with the measles virus in vitro.
    Hereditas. 1965;54(1):101-18 PMID: 5889255
  42. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism.
    J Cell Biol. 2010 Feb 8;188(3):369-81 PMID: 20123995
  43. MEL-28/ELYS is required for the recruitment of nucleoporins to chromatin and postmitotic nuclear pore complex assembly.
    EMBO Rep. 2007 Feb;8(2):165-72 PMID: 17235358
  44. Mechanisms of change in gene copy number.
    Nat Rev Genet. 2009 Aug;10(8):551-64 PMID: 19597530
  45. Systematic kinetic analysis of mitotic dis- and reassembly of the nuclear pore in living cells.
    J Cell Biol. 2008 Mar 10;180(5):857-65 PMID: 18316408
  46. Model for the formation of double minutes from prematurely condensed chromosomes of replicating micronuclei in drug-treated Chinese hamster ovary cells undergoing DNA amplification.
    Cancer Res. 1989 Dec 1;49(23):6731-7 PMID: 2819718
  47. Mammalian nuclei become licensed for DNA replication during late telophase.
    J Cell Sci. 2002 Jan 1;115(Pt 1):51-9 PMID: 11801723
  48. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139.
    J Biol Chem. 1998 Mar 6;273(10):5858-68 PMID: 9488723
  49. Dynamic organization of DNA replication in mammalian cell nuclei: spatially and temporally defined replication of chromosome-specific alpha-satellite DNA sequences.
    J Cell Biol. 1992 Mar;116(5):1095-110 PMID: 1740468
Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature10802
Published
2012-01-18
Epub
2012-00-18
Pages
53-8
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3271137
Subset
IM
Grants
NIGMS NIH HHS · R01 GM083299-14 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · 1R01CA142698-01 · United States
NCI NIH HHS · R00 CA154531 · United States
NIGMS NIH HHS · GM083299 · United States
NIGMS NIH HHS · R01 GM083299 · United States
NCI NIH HHS · R01 CA142698 · United States
Corrections
CommentIn
PMID: 22298192
CommentIn
PMID: 22298233
External Links
PubMed source DOI: 10.1038/nature10802 PMC Full Text View journal details
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