Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Functional mechanisms and abnormalities of the nuclear lamina

Abstract

Alterations in nuclear shape are present in human diseases and ageing. A compromised nuclear lamina is molecularly interlinked to altered chromatin functions and genomic instability. Whether these alterations are a cause or a consequence of the pathological state are important questions in biology. Here, we summarize the roles of nuclear envelope components in chromatin organization, phase separation and transcriptional and epigenetic regulation. Examining these functions in healthy backgrounds will guide us towards a better understanding of pathological alterations.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Nuclear architecture and chromatin organization of mammalian cells.
Fig. 2: Chromosomal organization and gene regulation through the NE components.
Fig. 3: The genomic and epigenomic alterations caused by NL abnormalities.

References

  1. 1.

    Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat. Rev. Mol. Cell Biol. 10, 75–82 (2009).

    CAS  PubMed  Google Scholar 

  2. 2.

    Butin-Israeli, V., Adam, S. A., Goldman, A. E. & Goldman, R. D. Nuclear lamin functions and disease. Trends Genet. 28, 464–471 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Andrés, V. & González, J. M. Role of A-type lamins in signaling, transcription, and chromatin organization. J. Cell Biol. 187, 945–957 (2009).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Raices, M. & D’Angelo, M. A. Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. Nat. Rev. Mol. Cell Biol. 13, 687–699 (2012).

    CAS  PubMed  Google Scholar 

  5. 5.

    Shoeman, R. L. & Traub, P. The in vitro DNA-binding properties of purified nuclear lamin proteins and vimentin. J. Biol. Chem. 265, 9055–9061 (1990).

    CAS  PubMed  Google Scholar 

  6. 6.

    Meuleman, W. et al. Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence. Genome Res. 23, 270–280 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Guelen, L. et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 453, 948–951 (2008).

    CAS  PubMed  Google Scholar 

  8. 8.

    Lund, E. G., Duband-Goulet, I., Oldenburg, A., Buendia, B. & Collas, P. Distinct features of lamin A-interacting chromatin domains mapped by ChIP-sequencing from sonicated or micrococcal nuclease-digested chromatin. Nucleus 6, 30–39 (2015).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Naetar, N., Ferraioli, S. & Foisner, R. Lamins in the nuclear interior—life outside the lamina. J. Cell Sci. 130, 2087–2096 (2017).

    CAS  PubMed  Google Scholar 

  10. 10.

    van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Vaquerizas, J. M. et al. Nuclear pore proteins nup153 and megator define transcriptionally active regions in the Drosophila genome. PLoS Genet. 6, e1000846 (2010).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kind, J. et al. Single-cell dynamics of genome–nuclear lamina interactions. Cell 153, 178–192 (2013).

    CAS  PubMed  Google Scholar 

  14. 14.

    Harr, J. C. et al. Directed targeting of chromatin to the nuclear lamina is mediated by chromatin state and A-type lamins. J. Cell Biol. 208, 33–52 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Bian, Q., Khanna, N., Alvikas, J. & Belmont, A. S. β-globin cis-elements determine differential nuclear targeting through epigenetic modifications. J. Cell Biol. 203, 767–783 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Borsos, M. et al. Genome–lamina interactions are established de novo in the early mouse embryo. Nature 569, 729–733 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Poleshko, A. et al. H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis. eLife 8, e49278 (2019).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Amendola, M. & Steensel, B. Nuclear lamins are not required for lamina‐associated domain organization in mouse embryonic stem cells. EMBO Rep. 16, 610–617 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Zheng, X., Kim, Y. & Zheng, Y. Identification of lamin B-regulated chromatin regions based on chromatin landscapes. Mol. Biol. Cell 26, 2685–2697 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zheng, X. et al. Lamins organize the global three-dimensional genome from the nuclear periphery. Mol. Cell 71, 802–815.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Akhtar, W. et al. Chromatin position effects assayed by thousands of reporters integrated in parallel. Cell 154, 914–927 (2013).

    CAS  PubMed  Google Scholar 

  22. 22.

    Reddy, K. L., Zullo, J. M., Bertolino, E. & Singh, H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008).

    CAS  PubMed  Google Scholar 

  23. 23.

    Czapiewski, R., Robson, M. I. & Schirmer, E. C. Anchoring a Leviathan: how the nuclear membrane tethers the genome. Front. Genet. 7, 82 (2016).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Chuang, C. H. et al. Long-range directional movement of an interphase chromosome site. Curr. Biol. 16, 825–831 (2006).

    CAS  PubMed  Google Scholar 

  25. 25.

    Therizols, P. et al. Chromatin decondensation is sufficient to alter nuclear organization in embryonic stem cells. Science 346, 1238–1242 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kumaran, R. I. & Spector, D. L. A genetic locus targeted to the nuclear periphery in living cells maintains its transcriptional competence. J. Cell Biol. 180, 51–65 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Brunet, A., Forsberg, F., Fan, Q., Sæther, T. & Collas, P. Nuclear lamin B1 interactions with chromatin during the circadian cycle are uncoupled from periodic gene expression. Front. Genet. 10, 917 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Wu, F. & Yao, J. Identifying novel transcriptional and epigenetic features of nuclear lamina-associated genes. Sci. Rep. 7, 100 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Leemans, C. et al. Promoter-intrinsic and local chromatin features determine gene repression in LADs. Cell 177, 852–864.e14 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Luperchio, T. et al. Chromosome conformation paints reveal the role of lamina association in genome organization and regulation. Preprint at bioRxiv https://doi.org/10.1101/122226 (2017).

  31. 31.

    Brueckner, L. et al. Local rewiring of genome–nuclear lamina interactions by transcription. EMBO J. 39, 1–17 (2020).

    Google Scholar 

  32. 32.

    Kuhn, T. M., Pascual-Garcia, P., Gozalo, A., Little, S. C. & Capelson, M. Chromatin targeting of nuclear pore proteins induces chromatin decondensation. J. Cell Biol. 218, 2945–2961 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Pascual-Garcia, P., Jeong, J. & Capelson, M. Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression. Cell Rep. 9, 433–442 (2014).

    CAS  PubMed  Google Scholar 

  34. 34.

    Raices, M. et al. Nuclear pores regulate muscle development and maintenance by assembling a localized Mef2C complex. Dev. Cell 41, 540–554.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Brickner, D. G. et al. The role of transcription factors and nuclear pore proteins in controlling the spatial organization of the yeast genome. Dev. Cell 49, 936–947.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ibarra, A., Benner, C., Tyagi, S., Cool, J. & Hetzer, M. W. Nucleoporin-mediated regulation of cell identity genes. Genes Dev. 30, 2253–2258 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Krull, S. et al. Protein Tpr is required for establishing nuclear pore-associated zones of heterochromatin exclusion. EMBO J. 29, 1659–1673 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    D’Urso, A. & Brickner, J. H. Epigenetic transcriptional memory. Curr. Genet. 63, 435–439 (2017).

    PubMed  Google Scholar 

  39. 39.

    Light, W. H., Brickner, D. G., Brand, V. R. & Brickner, J. H. Interaction of a DNA zip code with the nuclear pore complex promotes H2A.Z incorporation and INO1 transcriptional memory. Mol. Cell 40, 112–125 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Tan-Wong, S. M., Wijayatilake, H. D. & Proudfoot, N. J. Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex. Genes Dev. 23, 2610–2624 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Light, W. H. et al. A conserved role for human Nup98 in altering chromatin structure and promoting epigenetic transcriptional memory. PLoS Biol. 11, e1001524 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    D’Urso, A. et al. Set1/COMPASS and mediator are repurposed to promote epigenetic transcriptional memory. eLife 5, e16691 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Jacinto, F. V., Benner, C. & Hetzer, M. W. The nucleoporin Nup153 regulates embryonic stem cell pluripotency through gene silencing. Genes Dev. 29, 1224–1238 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Gozalo, A. et al. Core components of the nuclear pore bind distinct states of chromatin and contribute to polycomb repression. Mol. Cell 77, 67–81.e7 (2020).

    CAS  PubMed  Google Scholar 

  45. 45.

    Kalverda, B., Pickersgill, H., Shloma, V. V. & Fornerod, M. Nucleoporins directly stimulate expression of developmental and cell-cycle genes inside the nucleoplasm. Cell 140, 360–371 (2010).

    CAS  PubMed  Google Scholar 

  46. 46.

    Capelson, M. et al. Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes. Cell 140, 372–383 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Rabut, G., Doye, V. & Ellenberg, J. Mapping the dynamic organization of the nuclear pore complex inside single living cells. Nat. Cell Biol. 6, 1114–1121 (2004).

    CAS  PubMed  Google Scholar 

  48. 48.

    Strom, A. R. et al. Phase separation drives heterochromatin domain formation. Nature 547, 241–245 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Larson, A. G. et al. Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin. Nature 547, 236–240 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ye, Q., Callebaut, I., Pezhman, A., Courvalin, J.-C. & Worman, H. J. Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR. J. Biol. Chem. 272, 14983–14989 (1997).

    CAS  PubMed  Google Scholar 

  51. 51.

    Falk, M. et al. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 570, 395–399 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Aumiller, W. M. & Keating, C. D. Phosphorylation-mediated RNA/peptide complex coacervation as a model for intracellular liquid organelles. Nat. Chem. 8, 129–137 (2016).

    CAS  PubMed  Google Scholar 

  53. 53.

    von Appen, A. et al. LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation. Nature https://doi.org/10.1038/s41586-020-2232-x (2020).

  54. 54.

    Celetti, G. et al. The liquid state of FG-nucleoporins mimics permeability barrier properties of nuclear pore complexes. J. Cell Biol. 219, e201907157 (2020).

    PubMed  Google Scholar 

  55. 55.

    Koch, A. J. & Holaska, J. M. Emerin in health and disease. Semin. Cell Dev. Biol. 29, 95–106 (2014).

    CAS  PubMed  Google Scholar 

  56. 56.

    Kitten, G. T. & Nigg, E. A. The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2. J. Cell Biol. 113, 13–23 (1991).

    CAS  PubMed  Google Scholar 

  57. 57.

    Yang, S. H. et al. Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson–Gilford progeria syndrome mutation. Proc. Natl Acad. Sci. USA 102, 10291–10296 (2005).

    CAS  PubMed  Google Scholar 

  58. 58.

    Simon, D. N. & Wilson, K. L. Partners and post-translational modifications of nuclear lamins. Chromosoma 122, 13–31 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Fong, L. G. et al. Prelamin A and lamin A appear to be dispensable in the nuclear lamina. J. Clin. Invest. 116, 743–752 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Heitlinger, E. et al. Expression of chicken lamin B2 in Escherichia coli: characterization of its structure, assembly, and molecular interactions. J. Cell Biol. 113, 485–495 (1991).

    CAS  PubMed  Google Scholar 

  61. 61.

    Peter, M., Heitlinger, E., Häner, M., Aebi, U. & Nigg, E. A. Disassembly of in vitro formed lamin head-to-tail polymers by CDC2 kinase. EMBO J. 10, 1535–1544 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Eggert, M. et al. Identification of novel phosphorylation sites in murine A-type lamins. Eur. J. Biochem. 213, 659–671 (1993).

    CAS  PubMed  Google Scholar 

  63. 63.

    Goss, V. L. et al. Identification of nuclear βII protein kinase C as a mitotic lamin kinase. J. Biol. Chem. 269, 19074–19080 (1994).

    CAS  PubMed  Google Scholar 

  64. 64.

    Collas, P. Sequential PKC- and Cdc2-mediated phosphorylation events elicit zebrafish nuclear envelope disassembly. J. Cell Sci. 112, 977–987 (1999).

    CAS  PubMed  Google Scholar 

  65. 65.

    Thompson, L. J. & Fields, A. P. β II protein kinase C is required for the G2/M phase transition of cell cycle. J. Biol. Chem. 271, 15045–15053 (1996).

    CAS  PubMed  Google Scholar 

  66. 66.

    Collas, P., Thompson, L., Fields, A. P., Poccia, D. L. & Courvalin, J.-C. Protein kinase C-mediated interphase lamin B phosphorylation and solubilization. J. Biol. Chem. 272, 21274–21280 (1997).

    CAS  PubMed  Google Scholar 

  67. 67.

    Schmitz, M. H. A. et al. Live-cell imaging RNAi screen identifies PP2A-B55α and importin-β1 as key mitotic exit regulators in human cells. Nat. Cell Biol. 12, 886–893 (2010).

    CAS  PubMed  Google Scholar 

  68. 68.

    Mehsen, H. et al. PP2A-B55 promotes nuclear envelope reformation after mitosis in Drosophila. J. Cell Biol. 217, 4106–4123 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Kochin, V. et al. Interphase phosphorylation of lamin A. J. Cell Sci. 127, 2683–2696 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Kuga, T., Nozaki, N., Matsushita, K., Nomura, F. & Tomonaga, T. Phosphorylation statuses at different residues of lamin B2, B1, and A/C dynamically and independently change throughout the cell cycle. Exp. Cell Res. 316, 2301–2312 (2010).

    CAS  PubMed  Google Scholar 

  71. 71.

    Kolb, T. et al. Lamin A and lamin C form homodimers and coexist in higher complex forms both in the nucleoplasmic fraction and in the lamina of cultured human cells. Nucleus 2, 425–433 (2011).

    PubMed  Google Scholar 

  72. 72.

    Naetar, N. et al. Loss of nucleoplasmic LAP2α–lamin A complexes causes erythroid and epidermal progenitor hyperproliferation. Nat. Cell Biol. 10, 1341–1348 (2008).

    CAS  PubMed  Google Scholar 

  73. 73.

    Gesson, K. et al. A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha. Genome Res. 26, 462–473 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Ikegami, K., Secchia, S., Almakki, O., Lieb, J. D. & Moskowitz, I. P. Phosphorylated lamin A/C in the nuclear interior binds active enhancers associated with abnormal transcription in progeria. Dev. Cell 52, 699–713.e11 (2020).

    CAS  PubMed  Google Scholar 

  75. 75.

    Buxboim, A. et al. Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin. Curr. Biol. 24, 1909–1917 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Cho, S. et al. Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest. Dev. Cell 49, 920–935.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Schölz, C. et al. Acetylation site specificities of lysine deacetylase inhibitors in human cells. Nat. Biotechnol. 33, 415–423 (2015).

    PubMed  Google Scholar 

  78. 78.

    Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009).

    CAS  PubMed  Google Scholar 

  79. 79.

    Karoutas, A. et al. The NSL complex maintains nuclear architecture stability via lamin A/C acetylation. Nat. Cell Biol. 21, 1248–1260 (2019).

    CAS  PubMed  Google Scholar 

  80. 80.

    Taipale, M. et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol. Cell. Biol. 25, 6798–6810 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Chelmicki, T. et al. MOF-associated complexes ensure stem cell identity and Xist repression. eLife 3, e02024 (2014).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Zhang, Y.-Q. & Sarge, K. D. Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies. J. Cell Biol. 182, 35–39 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Simon, D. N., Domaradzki, T., Hofmann, W. A. & Wilson, K. L. Lamin A tail modification by SUMO1 is disrupted by familial partial lipodystrophy-causing mutations. Mol. Biol. Cell 24, 342–350 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Li, Y. et al. Nuclear accumulation of UBC9 contributes to SUMOylation of lamin A/C and nucleophagy in response to DNA damage. J. Exp. Clin. Cancer Res. 38, 67 (2019).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Kim, S.-J., Yoo, B. C., Uhm, C.-S. & Lee, S.-W. Posttranslational arginine methylation of lamin A/C during myoblast fusion. Biochim. Biophys. Acta Proteins Proteom. 1814, 308–317 (2011).

    CAS  Google Scholar 

  88. 88.

    Simon, D. et al. OGT (O-GlcNAc transferase) selectively modifies multiple residues unique to lamin A. Cells 7, 44 (2018).

    PubMed Central  Google Scholar 

  89. 89.

    Alfaro, J. F. et al. Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. Proc. Natl Acad. Sci. USA 109, 7280–7285 (2012).

    CAS  PubMed  Google Scholar 

  90. 90.

    Wang, Z. et al. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci. Signal. 3, ra2 (2010).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Pekovic, V. et al. Conserved cysteine residues in the mammalian lamin A tail are essential for cellular responses to ROS generation. Aging Cell 10, 1067–1079 (2011).

    CAS  PubMed  Google Scholar 

  92. 92.

    Fischer, A. H. in Cancer Biology and the Nuclear Envelope: Recent Advances May Elucidate Past Paradoxes (eds Schirmer, E. C. & de las Heras, J. I.) 49–75 (Springer New York, 2014).

  93. 93.

    Leibowitz, M. L., Zhang, C.-Z. & Pellman, D. Chromothripsis: a new mechanism for rapid karyotype evolution. Annu. Rev. Genet. 49, 183–211 (2015).

    CAS  PubMed  Google Scholar 

  94. 94.

    Zhang, C.-Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Korbel, J. O. & Campbell, P. J. Criteria for inference of chromothripsis in cancer genomes. Cell 152, 1226–1236 (2013).

    CAS  PubMed  Google Scholar 

  96. 96.

    Zhang, C.-Z., Leibowitz, M. L. & Pellman, D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 27, 2513–2530 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Hirsch, D. et al. Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Res. 73, 1454–1459 (2013).

    CAS  PubMed  Google Scholar 

  98. 98.

    Storchová, Z. & Kloosterman, W. P. The genomic characteristics and cellular origin of chromothripsis. Curr. Opin. Cell Biol. 40, 106–113 (2016).

    PubMed  Google Scholar 

  99. 99.

    Ly, P. & Cleveland, D. W. Rebuilding chromosomes after catastrophe: emerging mechanisms of chromothripsis. Trends Cell Biol. 27, 917–930 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Liu, S. et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561, 551–555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Samwer, M. et al. DNA cross-bridging shapes a single nucleus from a set of mitotic chromosomes. Cell 170, 956–972.e23 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Umbreit, N. T. et al. Mechanisms generating cancer genome complexity from a single cell division error. Science 368, eaba0712 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Hatch, E. M. Nuclear envelope rupture: little holes, big openings. Curr. Opin. Cell Biol. 52, 66–72 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Hatch, E. & Hetzer, M. Breaching the nuclear envelope in development and disease. J. Cell Biol. 205, 133–141 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Hatch, E. M. & Hetzer, M. W. Nuclear envelope rupture is induced by actin-based nucleus confinement. J. Cell Biol. 215, 27–36 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Maciejowski, J. & Hatch, E. M. Nuclear membrane rupture and its consequences. Annu. Rev. Cell Dev. Biol. 36, 85–114 (2020).

    CAS  PubMed  Google Scholar 

  107. 107.

    Ghosh, S., Liu, B., Wang, Y., Hao, Q. & Zhou, Z. Lamin A is an endogenous SIRT6 activator and promotes SIRT6-mediated DNA repair. Cell Rep. 13, 1396–1406 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Skourti-Stathaki, K. et al. R-loops enhance polycomb repression at a subset of developmental regulator genes. Mol. Cell 73, 930–945.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Bell, E. S. & Lammerding, J. Causes and consequences of nuclear envelope alterations in tumour progression. Eur. J. Cell Biol. 95, 449–464 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Wolberg, W. H., Street, W. N. & Mangasarian, O. L. Importance of nuclear morphology in breast cancer prognosis. Clin. Cancer Res. 5, 3542–3548 (1999).

    CAS  PubMed  Google Scholar 

  111. 111.

    Papanicolaou, G. N. & Traut, H. F. The diagnostic value of vaginal smears in carcinoma of the uterus. Am. J. Obstet. Gynecol. 42, 193–206 (1941).

    Google Scholar 

  112. 112.

    Harada, T. et al. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J. Cell Biol. 204, 669–682 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Kong, L. et al. Lamin A/C protein is overexpressed in tissue-invading prostate cancer and promotes prostate cancer cell growth, migration and invasion through the PI3K/AKT/PTEN pathway. Carcinogenesis 33, 751–759 (2012).

    CAS  PubMed  Google Scholar 

  114. 114.

    Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2011).

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Vandiver, A. R. et al. Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin. Genome Biol. 16, 80 (2015).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Rodríguez-Paredes, M. et al. Methylation profiling identifies two subclasses of squamous cell carcinoma related to distinct cells of origin. Nat. Commun. 9, 577 (2018).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Zhou, W. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet. 50, 591–602 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Smith, K. S., Liu, L. L., Ganesan, S., Michor, F. & De, S. Nuclear topology modulates the mutational landscapes of cancer genomes. Nat. Struct. Mol. Biol. 24, 1000–1006 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    García‐Nieto, P. E. et al. Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis. EMBO J. 36, 2829–2843 (2017).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Hsu, T. C. A possible function of constitutive heterochromatin: the bodyguard hypothesis. Genetics 79, 137–150 (1975).

    PubMed  Google Scholar 

  121. 121.

    Lemaître, C. et al. Nuclear position dictates DNA repair pathway choice. Genes Dev. 28, 2450–2463 (2014).

    PubMed  PubMed Central  Google Scholar 

  122. 122.

    López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Shimi, T. et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 25, 2579–2593 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Freund, A., Laberge, R.-M., Demaria, M. & Campisi, J. Lamin B1 loss is a senescence-associated biomarker. Mol. Biol. Cell 23, 2066–2075 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Lenain, C. et al. Massive reshaping of genome–nuclear lamina interactions during oncogene-induced senescence. Genome Res. 27, 1634–1644 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Spektor, A., Umbreit, N. T. & Pellman, D. Cell biology: when your own chromosomes act like foreign DNA. Curr. Biol. 27, R1228–R1231 (2017).

    CAS  PubMed  Google Scholar 

  127. 127.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Gladyshev, T. V. & Gladyshev, V. N. A disease or not a disease? Aging as a pathology. Trends Mol. Med. 22, 995–996 (2016).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Zhang, W. et al. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348, 1160–1163 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e12 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Dittmer, T. A. & Misteli, T. The lamin protein family. Genome Biol. 12, 222 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Schreiber, K. H. & Kennedy, B. K. When lamins go bad: nuclear structure and disease. Cell 152, 1365–1375 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).

    CAS  PubMed  Google Scholar 

  134. 134.

    Scaffidi, P. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Shumaker, D. K. et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc. Natl Acad. Sci. USA 103, 8703–8708 (2006).

    CAS  PubMed  Google Scholar 

  136. 136.

    Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 101, 8963–8968 (2004).

    CAS  PubMed  Google Scholar 

  137. 137.

    McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson–Gilford progeria syndrome. Genome Res. 23, 260–269 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Köhler, F. et al. Epigenetic deregulation of lamina-associated domains in Hutchinson–Gilford progeria syndrome. Genome Med. 12, 46 (2020).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Pegoraro, G. et al. Ageing-related chromatin defects through loss of the NURD complex. Nat. Cell Biol. 11, 1261–1267 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Paulsen, J. et al. Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts. Genome Biol. 18, 21 (2017).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Akhtar, A. & Gasser, S. M. The nuclear envelope and transcriptional control. Nat. Rev. Genet. 8, 507–517 (2007).

    CAS  PubMed  Google Scholar 

  142. 142.

    Ibarra, A. & Hetzer, M. W. Nuclear pore proteins and the control of genome functions. Genes Dev. 29, 337–349 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Local, A. et al. Identification of H3K4me1-associated proteins at mammalian enhancers. Nat. Genet. 50, 73–82 (2018).

    CAS  PubMed  Google Scholar 

  144. 144.

    Marini, B. et al. Nuclear architecture dictates HIV-1 integration site selection. Nature 521, 227–233 (2015).

    CAS  PubMed  Google Scholar 

  145. 145.

    Meyerson, M. & Pellman, D. Cancer genomes evolve by pulverizing single chromosomes. Cell 144, 9–10 (2011).

    CAS  PubMed  Google Scholar 

  146. 146.

    Mitchell, T. J. et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell 173, 611–623.e17 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Ward, G. E. & Kirschner, M. W. Identification of cell cycle-regulated phosphorylation sites on nuclear lamin C. Cell 61, 561–577 (1990).

    CAS  PubMed  Google Scholar 

  148. 148.

    Heald, R. & McKeon, F. Mutations of phosphorylation sites in lamin A that prevent nuclear lamina disassembly in mitosis. Cell 61, 579–589 (1990).

    CAS  PubMed  Google Scholar 

  149. 149.

    Borroni, A. P. et al. Smurf2 regulates stability and the autophagic-lysosomal turnover of lamin A and its disease-associated form progerin. Aging Cell 17, e12732 (2018).

    PubMed Central  Google Scholar 

Download references

Acknowledgements

We are thankful to M. Shvedunova, M. Samata, M. Wiese, I. Grządzielewska and A. Apostolidou for carefully reading and commenting on the manuscript. Research in the Akhtar Lab is funded by the Max Planck Society and the Deutsche Forschungsgemeinschaft (DFG) through collaborative research grants SFB 992, SFB 1381, SFB 1425 and the CIBSS Cluster of Excellence (EXC-2189).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Asifa Akhtar.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Karoutas, A., Akhtar, A. Functional mechanisms and abnormalities of the nuclear lamina. Nat Cell Biol 23, 116–126 (2021). https://doi.org/10.1038/s41556-020-00630-5

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing