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Help or hindrance: how do microtubule-based forces contribute to genome damage and repair?

  • Cassi Estrem
  • Jeffrey K. MooreEmail author
Mini-Review

Abstract

Forces generated by molecular motors and the cytoskeleton move the nucleus and genome during many cellular processes, including cell migration and division. How these forces impact the genome, and whether cells regulate cytoskeletal forces to preserve genome integrity is unclear. We recently demonstrated that, in budding yeast, mutants that stabilize the microtubule cytoskeleton cause excessive movement of the mitotic spindle and nucleus. We found that increased nuclear movement results in DNA damage and increased time to repair the damage through homology-directed repair. Our results indicate that nuclear movement impairs DNA repair through increased tension on chromosomes and nuclear deformation. However, the previous studies have shown genome mobility, driven by cytoskeleton-based forces, aids in homology-directed DNA repair. This sets up an apparent paradox, where genome mobility may prevent or promote DNA repair. Hence, this review explores how the genome is affected by nuclear movement and how genome mobility could aid or hinder homology-directed repair.

Keywords

DNA damage HDR Dynein Microtubule Cytoskeleton Nucleus 

Notes

Acknowledgements

This work was supported by National Institutes of Health Grant no. R01GM-112893 (to J.K.M.).

References

  1. Abal M, Andreu JM, Barasoain I (2003) Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targ 3(3):193–203Google Scholar
  2. Baffet AD, Hu DJ, Vallee RB (2015) Cdk1 activates pre-mitotic nuclear envelope dynein recruitment and apical nuclear migration in neural stem cells. Dev Cell 33(6):703–716Google Scholar
  3. Berre LE, Maël JA, Piel Matthieu (2012) fine control of nuclear confinement identifies a threshold deformation leading to lamina rupture and induction of specific genes. Integr Biol 4(11):1406Google Scholar
  4. Bhalla KN (2003) Microtubule-targeted anticancer agents and apoptosis. Oncogene 22(56):9075–9086Google Scholar
  5. Bordelet H, Dubrana Karine (2019) Keep moving and stay in a good shape to find your homologous recombination partner. Curr Genet 65(1):29–39.  https://doi.org/10.1007/s00294-018-0873-1 Google Scholar
  6. Brangwynne CP et al (2006) Microtubules can bear enhanced compressive loads in living cells because of lateral reinforcement. J Cell Biol 173(5):733–741Google Scholar
  7. Broers JLV, Hutchison CJ, Ramaekers FCS (2004) Laminopathies. J Pathol 204(4):478–488Google Scholar
  8. Bupp JM, Martin AE, Stensrud ES, Jaspersen SL (2007) Telomere anchoring at the nuclear periphery requires the budding yeast Sad1-UNC-84 domain protein Mps3. J Cell Biol 179(5):845–854Google Scholar
  9. Byers B, Goetsch L (1975) Behavior of spindles and spindle plaques in the cell cycle and conjugation of saccharomyces cerevisiae. J Bacteriol 124(1):511–523Google Scholar
  10. Canman JC et al (2003) Determining the position of the cell division plane. Nature 424(6952):1074–1078Google Scholar
  11. Carminati Janet L, Stearns T (1997) Microtubules orient the mitotic spindle in yeast through dynein- dependent interactions with the cell cortex. J Cell Biol 138(3):629–641Google Scholar
  12. Chikashige Y et al (1994) Telomere-led premeiotic chromosome movement in fission yeast. Science 264(5156):270–273.  https://doi.org/10.1126/science.8146661 Google Scholar
  13. Chow KH, Factor RE, Ullman KS (2012) The nuclear envelope environment and its cancer connections. Nat Rev Cancer 12(3):196–209Google Scholar
  14. Chung DKC et al (2015) Perinuclear tethers license telomeric dsbs for a broad kinesin- and npc-dependent dna repair process. Nat Commun 6(1):7742Google Scholar
  15. Conrad MN et al (2008) Rapid telomere movement in meiotic prophase is promoted by NDJ1, MPS3, and CSM4 and is modulated by recombination. Cell 133(7):1175–1187Google Scholar
  16. Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D (2006) Coupling of the nucleus and cytoplasm: role of the LINC complex. J Cell Biol 172:41–53Google Scholar
  17. Dahl KN, Kahn SM, Wilson KL, Discher DE (2004) The nuclear envelope lamina network has elasticity and a compressibility limit suggestive of a molecular shock absorber. J Cell Sci 117(Pt 20):4779–4786Google Scholar
  18. Denais CM et al (2016) Nuclear envelope rupture and repair during cancer cell migration. Science 352(6283):353–358Google Scholar
  19. Ding DQ, Yamamoto A, Haraguchi T, Hiraoka Y (2004) Dynamics of homologous chromosome pairing during meiotic prophase in fission yeast. Dev Cell 6(3):329–341Google Scholar
  20. Dotiwala F et al (2007) The yeast DNA damage checkpoint proteins control a cytoplasmic response to DNA damage. Proc Natl Acad Sci USA 104:11358–11363Google Scholar
  21. Ecklund KH et al (2017) She1 affects dynein through direct interactions with the microtubule and the dynein microtubule-binding domain. Nat Commun 8(1):2151Google Scholar
  22. Eshel D, Urrestarazu LA, Vissers S, Jauniaux JC, van Vliet-Reedijk JC, Planta RJ, Gibbons IR (1993) Cytoplasmic dynein is required for normal nuclear segregation in yeast. Proc Natl Acad Sci U S A 90:11172–11176Google Scholar
  23. Estrem C, Moore JK (2019) Astral microtubule forces alter nuclear organization and inhibit dna repair in budding yeast. Mol Biol Cell 30(6):2000–2013Google Scholar
  24. Estrem C, Fees CP, Moore JK (2017) Dynein is regulated by the stability of its microtubule track. J Cell Biol 216(7):2047–2058Google Scholar
  25. Fanale D et al (2015) Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option? Anal Cell Pathol 2015:1–19Google Scholar
  26. Fees CP et al (2016) The negatively charged carboxy-terminal tail of β-tubulin promotes proper chromosome segregation. Mol Biol Cell 27(11):1786–1796.  https://doi.org/10.1091/mbc.E15-05-0300 Google Scholar
  27. Fletcher DA, Mullins RD (2010) Cell mechanics and the cytoskeleton. Nature 463(7280):485–492Google Scholar
  28. Goshima G, Yanagida Mitsuhiro (2000) Establishing biorientation occurs with precocious separation of the sister kinetochores, but not the arms, in the early spindle of budding yeast. Cell 100(6):619–633Google Scholar
  29. Green RA, Paluch E, Oegema Karen (2012) Cytokinesis in animal cells. Annu. Rev. Cell Dev. Biol 28:29–58Google Scholar
  30. Hatch EM, Hetzer MW (2016) Nuclear envelope rupture is induced by actin-based nucleus confinement. J Cell Biol 215(1):27–36Google Scholar
  31. Hediger F et al (2002) Live imaging of telomeres: yku and sir proteins define redundant telomere-anchoring pathways in yeast. Curr Biol 12(24):2076–2089Google Scholar
  32. Hetzer MW (2010) The nuclear envelope. Cold Spring Harbor Perspect Biol 2(3):1–6Google Scholar
  33. Ho CY, Lammerding J (2012) Lamins at a glance. J Cell Sci 125(9):2087–2093.  https://doi.org/10.1242/jcs.087288 Google Scholar
  34. Hornberger TA et al (2005) Intracellular signaling specificity in response to uniaxial vs. multiaxial stretch: implications for mechanotransduction. Am J Physiol-Cell Physiol 288(1):C185–C194.  https://doi.org/10.1152/ajpcell.00207.2004 Google Scholar
  35. Irianto J et al (2017) DNA damage follows repair factor depletion and portends genome variation in cancer cells after pore migration. Curr Biol 27(2):210–223Google Scholar
  36. Ivanov EL et al (1994) Mutations in XRS2 and RAD50 delay but do not prevent mating-type switching in Saccharomyces cerevisiae. Mol Cell Biol 14(5):3414–3425Google Scholar
  37. Jablonski SA, Liu ST, Yen TJ (2003) Targeting the kinetochore for mitosis-specific inhibitors. Cancer Biol Ther 2(3):236–241Google Scholar
  38. Jasin M, Berg P (1988) Homologous integration in mammalian cells without target gene selection. Genes Dev 2(11):1353–1363Google Scholar
  39. Knaus M et al (2005) The Bud14p-Glc7p complex functions as a cortical regulator of dynein in budding yeast. EMBO J 24(17):3000–3011Google Scholar
  40. Koszul R, Kleckner Nancy (2009) Dynamic chromosome movements during meiosis: a way to eliminate unwanted connections? Trends Cell Biol 19(12):716–724Google Scholar
  41. Labrador L et al (2013) “Chromosome movements promoted by the mitochondrial protein spd-3 are required for homology search during caenorhabditis elegans meiosis” ed. mónica P. Colaiácovo. PLoS Genet 9(5):e1003497Google Scholar
  42. Lawrimore J et al (2017) Microtubule dynamics drive enhanced chromatin motion and mobilize telomeres in response to DNA damage. Mol Biol Cell 28(12):1701–1711.  https://doi.org/10.1091/mbc.E16-12-0846 Google Scholar
  43. Lee CS et al (2016) Chromosome position determines the success of double-strand break repair. Proc Natl Acad Sci 113(2):E146–E154Google Scholar
  44. Li YY, Yeh E, Hays T, Bloom K (1993) Disruption of mitotic spindle orientation in a yeast dynein mutant. Proc Natl Acad Sci 90:10096–10100Google Scholar
  45. Liu J et al (2000) “Essential roles for caenorhabditis elegans lamin gene in nuclear organization, cell cycle progression, and spatial organization of nuclear pore complexes” ed joseph gall. Mol Biol Cell 11(11):3937–3947.  https://doi.org/10.1091/mbc.11.11.3937 Google Scholar
  46. Loeb LA, Springgate CF, Battula N (1974) Errors in DNA replication as a basis of malignant changes. Cancer Res 34:2311–2321Google Scholar
  47. Lottersberger F, Karssemeijer RA, Dimitrova Nadya, de Lange T (2015) 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 163(4):880–893Google Scholar
  48. Parvinen M, Soderstrom KO (1976) Chromosome rotation and formation of synapsis. Nature 260(5551):534–535Google Scholar
  49. Miller M, Granzier H, Ehler E, Gregorio CC (2004) The sensitive giant: the role of titin-based stretch sensing complexes in the heart. Trends Cell Biol 14(3):119–126Google Scholar
  50. Mimitou EP, Symington LS (2010) Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J 29:3358–3369Google Scholar
  51. Miné-Hattab J, Rothstein R (2012) Increased chromosome mobility facilitates homology search during recombination. Nat Cell Biol 14(5):510–517Google Scholar
  52. Moore JK, Sept D, Cooper JA (2009) Neurodegeneration Mutations in Dynactin Impair Dynein-Dependent Nuclear Migration. Proc Natl Acad Sci 106:5147–5152Google Scholar
  53. Moriel-Carretero M, Pasero P, Pardo B (2019) DDR Inc., one business, two associates. Curr Genet 65(2):445–451Google Scholar
  54. Muhua L, Karpova TS, Cooper JA (1994) A yeast actin-related protein homologous to that in vertebrate dynactin complex is important for spindle orientation and nuclear migration. Cell 78:669–679Google Scholar
  55. Ng TM, Waples WG, Lavoie BD, Biggins S (2009) Pericentromeric sister chromatid cohesion promotes kinetochore biorientation. Mol Biol Cell 20:3818–3827.  https://doi.org/10.1091/mbc.E09 Google Scholar
  56. Nowell P (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28Google Scholar
  57. Olenick MA, Holzbaur EL (2019) Dynein activators and adaptors at a glance. J cell Sci.  https://doi.org/10.1242/jcs.227132 Google Scholar
  58. Orr-Weaver TL, Szostak JW, Rothstein RJ (1981) Yeast transformation: a model system for the study of recombination. Proc Natl Acad Sci 78(10):6354–6358.  https://doi.org/10.1073/pnas.78.10.6354 Google Scholar
  59. Oshidari R et al (2018) Nuclear microtubule filaments mediate non-linear directional motion of chromatin and promote dna repair. Nat commun 9(1):2567Google Scholar
  60. Penfield L et al (2018) Dynein-pulling forces counteract lamin-mediated nuclear stability during nuclear envelope repair. Mol Biol Cell.  https://doi.org/10.1091/mbc.E17-06-0374 Google Scholar
  61. Phillips M et al (2009) Identification of chromosome sequence motifs that mediate meiotic pairing and synapsis in c. elegans. Nat Cell Biol 11(8):934–942Google Scholar
  62. Raab M et al (2016) ESCRT III repairs nuclear envelope ruptures during cell migration to limit dna damage and cell death. Science 352(6283):359–362Google Scholar
  63. Rankin KE, Wordeman Linda (2010) long astral microtubules uncouple mitotic spindles from the cytokinetic furrow. J Cell Biol 190(1):35–43Google Scholar
  64. Raspelli E, Fraschini Roberta (2019) Spindle pole power in health and disease. Curr Genet 65(4):851–855Google Scholar
  65. Reck-Peterson SL, Redwine William B, Vale Ronald D, Carter Andrew P (2018) The cytoplasmic dynein transport machinery and its many cargoes. Nat Rev Mol Cell Biol 19(6):382–398Google Scholar
  66. Rogakou EP et al (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868Google Scholar
  67. Sassoon I et al (1999) Regulation of Saccharomyces cerevisiae kinetochores by the type 1 phosphatase Glc7p. Genes Dev 13(5):545–555Google Scholar
  68. Sato A et al (2009) Cytoskeletal forces span the nuclear envelope to coordinate meiotic chromosome pairing and synapsis. Cell 139(5):907–919Google Scholar
  69. Scherthan H et al (2007) Chromosome mobility during meiotic prophase in Saccharomyces cerevisiae. Proc Natl Acad Sci 104(43):16934–16939Google Scholar
  70. Schober H et al (2009) Yeast telomerase and the sun domain protein Mps3 anchor telomeres and repress subtelomeric recombination. Genes Dev 23(8):928–938Google Scholar
  71. Schroer TA (2000) Motors, clutches and brakes for membrane traffic: a commemorative review in honor of thomas kreis. Traffic 1(1):3–10Google Scholar
  72. Shah P, Wolf K, Lammerding J (2017) Bursting the bubble–nuclear envelope rupture as a path to genomic instability? Trends Cell Biol 27(8):546–555Google Scholar
  73. Snijders BL et al (2015) “Mutations in DDX3X are a common cause of unexplained intellectual disability with gender-specific effects on wnt signaling. Am J Hum Genet 97(2):343–352Google Scholar
  74. Snyder J, Mullins JM (1993) Analysis of spindle microtubule organization in untreated and taxol-treated PtK1 cells. Cell Biol Int 17(12):1075–1084Google Scholar
  75. Sorger PK, Dobles M, Tournebize R, Hyman AA (1997) Coupling cell division and cell death to microtubule dynamics. Curr Opin Cell Biol 9(6):807–814Google Scholar
  76. Soria G, Polo SE, Almouzni G (2012) Prime, repair, restore: the active role of chromatin in the DNA damage response. Mol Cell 46(6):722–734Google Scholar
  77. Strecker J et al (2016) DNA damage signalling targets the kinetochore to promote chromatin mobility. Nat Cell Biol 18(3):281–290Google Scholar
  78. Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW (1983) The double-strand-break repair model for recombination. Cell 33(1):25–35Google Scholar
  79. Tubbs A, Nussenzweig A (2017) Endogenous DNA damage as a source of genomic instability in cancer. Cell 168:644–656Google Scholar
  80. Devi Tangutur A, Kumar D, Krishna KV, Kantevari S (2017) Microtubule targeting agents as cancer chemotherapeutics: an overview of molecular hybrids as stabilizing and destabilizing agents. Curr Top Med Chem 17(22):2523–2537Google Scholar
  81. Verdaasdonk JS et al (2013) Centromere tethering confines chromosome domains. Mol Cell 52(6):819–831Google Scholar
  82. De vos WH et al (2011) Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. Hum Mol Genet 20(21):4175–4186Google Scholar
  83. Wang TH, Wang HS, Soong YK (2000) Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 88(11):2619–2628Google Scholar
  84. Willardsen MI, Link BA (2011) Cell biological regulation of division fate in vertebrate neuroepithelial cells. Dev Dyn 240(8):1865–1879Google Scholar
  85. Woglar A, Jantsch V (2014) Chromosome movement in meiosis I prophase of Caenorhabditis elegans. Chromosoma 123(1–2):15–24Google Scholar
  86. Woodruff JB, Drubin DG, Barnes G (2009) Dynein-driven mitotic spindle positioning restricted to anaphase by She1p inhibition of dynactin recruitment dynein is a minus-end-directed microtubule motor important for mitotic spindle positioning. Mol Biol Cell. 20(13):3003–3011Google Scholar
  87. Wu N, Yu H (2012) The Smc complexes in DNA damage response. Cell Biosci.  https://doi.org/10.1186/2045-3701-2-5 Google Scholar
  88. Wynne DJ, Rog O, Carlton PM, Dernburg AF (2012) Dynein-dependent processive chromosome motions promote homologous pairing in C. elegans meiosis. J Cell Biol 196(1):47–64Google Scholar
  89. Xia Y et al (2019) Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle. J Cell Biol.  https://doi.org/10.1083/jcb.201811100 Google Scholar
  90. Yamamoto A, West RR, McIntosh JR, Hiraoka Y (1999) A cytoplasmic dynein heavy chain is required for oscillatory nuclear movement of meiotic prophase and efficient meiotic recombination in fission yeast. J Cell Biol 145(6):1233–1249Google Scholar
  91. Yeh E (1995) Spindle dynamics and cell cycle regulation of dynein in the budding yeast, Saccharomyces cerevisiae. J Cell Biol 130(3):687–700.  https://doi.org/10.1083/jcb.130.3.687 Google Scholar
  92. Yu J et al (2011) KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development. Hum Mol Genet 20(6):1061–1073Google Scholar
  93. Zhang X et al (2009) SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice. Neuron 64(2):173–187Google Scholar
  94. Zimmer C, Fabre E (2019) Chromatin mobility upon DNA damage: state of the art and remaining questions. Curr Genet 65(1):1–9Google Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cell and Developmental BiologyUniversity of Colorado School of MedicineAuroraUSA
  2. 2.Department of Brain and Cognitive SciencesMassachusetts Institute of TechnologyCambridgeUSA

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