Chromosome segregation errors: a double-edged sword - TI Pharma

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Chapter 2 Chromosome Segregation Errors as a Cause of DNA Damage and Structural Chromosome Aberrations Aniek Janssen 1,4 , Marja van der Burg 2 , Karoly Szuhai 2 , Geert J.P.L. Kops 1,3,5 , René H. Medema 1,4,5. 1 Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands, 2 Department of Molecular Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2300RC Leiden, the Netherlands, 3 Department of Molecular Cancer Research and Cancer Genomics Center, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, the Netherlands. 4 Division of Cell Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands. Science. 2011 Sep 30;333(6051):1895-8 31 Chromosome Segregation Errors cause DNA Damage 2
2 Abstract Various types of chromosomal aberrations, including numerical (aneuploidy) and structural (e.g. translocations, deletions), are commonly found in human tumors and are linked to tumorigenesis. Aneuploidy is a direct consequence of chromosome segregation errors in mitosis, while structural aberrations are caused by improperly repaired DNA breaks. Here we demonstrate that chromosome segregation errors can also result in structural chromosome aberrations. Chromosomes that missegregate are frequently damaged during cytokinesis, triggering a DNA double strand break response in the respective daughter cells involving ATM, Chk2 and p53. We show that these double strand breaks can lead to unbalanced translocations in the daughter cells. Our data show that segregation errors can cause translocations and provide novel insights on the role of wholechromosome instability in tumorigenesis. 32
Page 2 and 3: Chromosome segregation errors: a do
Page 4 and 5: Chromosome segregation errors: a do
Page 6: Get up, stand up, stand up for your
Page 10 and 11: Chapter 1 General Introduction Anie
Page 12 and 13: cytoplasms and pinches off the memb
Page 14 and 15: which sister-chromatids are not pro
Page 16 and 17: Non-MCC members, but important mito
Page 18 and 19: completely separated. Following cle
Page 20 and 21: Two striking features of cancer cel
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Page 24 and 25: that aberrant spindle formation inc
Page 26 and 27: (Fig.7C). As discussed in section 4
Page 28 and 29: Thesis outline Chromosome segregati
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Page 35 and 36: 2 34 A C D E % of cells Control 100
Page 37 and 38: 2 assess whether cytokinesis induce
Page 39 and 40: 2 A Asynchronous Monastrol release
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Page 43 and 44: 2 Immuno Blotting Cells were lysed
Page 45 and 46: 2 Supplemental figures 44 A B C % o
Page 47 and 48: 2 A MCF7 B C 53BP1 foci/cell 46 % o
Page 49 and 50: 2 A siLuc siATM C 48 p-S1981 ATM me
Page 51 and 52: 2 50 A B C % of EdU positive cells
Page 54 and 55: Chapter 3 Studying Chromosomal inst
Page 56 and 57: Introduction Aneuploidy is a common
Page 58 and 59: activity by ~80% 170-172 . With the
Page 60 and 61: A WT/CiMKi T649A Embryo’s: Figure
Page 62 and 63: control treated MEFs (unpaired t te
Page 64 and 65: Materials and Methods Cloning targe
Page 66 and 67: - Loop out BamHI site with site-dir
Page 68 and 69: Primers: pGH_pA_FW#2: TCTATGGCTTCTG
Page 70 and 71: was prepared using standard procedu
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Page 75 and 76: 4 Abstract Most of the current drug
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4 cluster their centrosomes. This
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4 of checkpoint function can be ach
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4 4.5 Disadvantages of exploiting m
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Chapter 5 Elevating the frequency o
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Introduction Error-free chromosome
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Partial depletion of Mps1 or BubR1
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death is not induced in the short t
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had survived growth for 7 days in t
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The following antibodies have been
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Supplemental data Supplemental figu
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A BubR1 α-tubulin Hela-TetRBubR1 -
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- doxycycline + doxycycline - doxyc
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A B C percentage of cells % PI posi
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Abstract One of the most common hal
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clear accumulation of cells in mito
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the mice did not receive any doxycy
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113 Chromosome missegregations kill
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Chapter 6 Aneuploid tumor cells are
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Introduction Equal segregation of t
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S1A, data not shown). Based on thes
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A B U2OS + H2B-YFP percentage of ce
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tumor cells, leaving diploid cells
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A B p-S10-Histone H3 DAPI C µmol/l
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Supplemental Figure-1. Protein bioc
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Bioavailability of compound-5 after
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A B U2OS (7.5nM) Hela (10nM) RPE-1
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7 Abstract Taxanes, such as docetax
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7 of mitotic aberrations. These dat
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7 A Low CFP lifetime High CFP lifet
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7 docetaxel treatment in vitro resu
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7 chromosome unstable, which means
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7 Cells (~50.000/well) were plated
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7 Supplemental data Supplemental fi
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7 148
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8 Thesis summary Unequal separation
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8 exerted through contraction of th
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8 1.4 NoCut: preventing the inducti
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8 tumorformation using intravital i
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Addendum References Nederlandse sam
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41. McEwen, B.F., et al., CENP-E is
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2010. 6(5): p. 359-68. 124. Liu, S.
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210. Stucki, M., et al., MDC1 direc
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tumors in mice. Cancer Res, 2007. 6
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adiotherapy in breast cancer. Breas
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470. Marcus, A.I., et al., Mitotic
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559. Kienitz, A., et al., Partial d
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Nederlandse Samenvatting Celdeling,
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verdeling van tumorcellen compleet
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Publications A. Janssen, R.H.Medema
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En dan zijn er nu nog een aantal li
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promotie-stukjes! Je bent een voorb
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edankt voor al jullie hulp bij de i
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Chromosome segregation errors: a double-edged sword - TI Pharma

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