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Rotten to the Core: Why Micronuclei Rupture

2018; Elsevier BV; Volume: 47; Issue: 3 Linguagem: Inglês

10.1016/j.devcel.2018.10.023

1878-1551

C. Patrick Lusk, Megan C. King,

Boron Compounds in Chemistry

A recent study in Nature from Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar suggests that the rupture of micronuclei and resulting exposure of genomic DNA to the cytosol is driven by microtubule-induced defects in the biochemical composition of their bounding membranes. A recent study in Nature from Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar suggests that the rupture of micronuclei and resulting exposure of genomic DNA to the cytosol is driven by microtubule-induced defects in the biochemical composition of their bounding membranes. The physical segregation of the genome inside a sealed nuclear envelope evolved concurrently with machinery that could tie transcription and translation to distinct nuclear and cytoplasmic compartments. It is therefore intuitive that conditions leading to loss of nuclear-cytoplasmic compartmentalization are detrimental to the cell. Perhaps less anticipated are findings that defects in chromosome segregation during mitosis can lead to the formation of "micronuclei" through the enclosure of lagging chromosomes within membranes (Hatch et al., 2013Hatch E.M. Fischer A.H. Deerinck T.J. Hetzer M.W. Catastrophic nuclear envelope collapse in cancer cell micronuclei.Cell. 2013; 154: 47-60Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). The rupture of these micronuclei can lead to the exposure of genomic DNA to the cytosol, triggering nucleic acid-sensing innate immune pathways. Further, chromosomes that form micronuclei often accumulate DNA damage and undergo extensive genomic rearrangements through an ill-defined process termed "chromothripsis" (Zhang et al., 2015Zhang C.-Z. Spektor A. Cornils H. Francis J.M. Jackson E.K. Liu S. Meyerson M. Pellman D. Chromothripsis from DNA damage in micronuclei.Nature. 2015; 522: 179-184Crossref PubMed Scopus (666) Google Scholar). These "shattered" chromosomes might be an underlying cause of the genetic instability inherent in cancer cell genomes. Defining how and why micronuclei rupture will therefore broadly inform mechanisms that contribute to chromothripsis, cellular senescence, inflammation, and even the sensitivity of cancer cells to immunotherapy. In an exciting new study by Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar, the underlying basis for the instability of micronuclei is systematically explored by first examining their biochemical composition during nuclear envelope reassembly in synchronized cell populations (Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar). Strikingly, the authors found that micronuclei recruit an altered complement of nuclear envelope membrane proteins, lacking some factors while possessing high levels of others, compared to the primary nucleus within the same cell (Figure 1). The enriched subset, which includes LAP2α, and emerin, two founding members of the "LEM" domain proteins, localize to the so-called "core" region of a re-assembling nucleus at the end of mitosis (Figure 1, red membranes). The spatial segregation of core and "non-core" (Figure 1, blue membranes) nuclear envelope proteins, the latter of which includes nuclear pore complexes (NPCs), has been observed for nearly 20 years (Haraguchi et al., 2000Haraguchi T. Koujin T. Hayakawa T. Kaneda T. Tsutsumi C. Imamoto N. Akazawa C. Sukegawa J. Yoneda Y. Hiraoka Y. Live fluorescence imaging reveals early recruitment of emerin, LBR, RanBP2, and Nup153 to reforming functional nuclear envelopes.J. Cell Sci. 2000; 113: 779-794Crossref PubMed Google Scholar). However, what underlies this physical segregation, and the functional consequences of this organization (if any), has remained enigmatic. That micronuclei appear enriched in core proteins suggests that there are features of these lagging chromosomes, or their environment, that favor recruitment of core-containing membranes and/or disfavor recruitment of non-core membranes. Moreover, this observation neatly predicts that this imbalance may promote rupture and strongly suggests that the mechanisms underlying core and non-core segregation are key to building stable nuclei. In a series of elegant experiments, Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar test the hypothesis that the altered composition of micronuclei reflects the "geography" of chromosome segregation. Indeed, micronuclei are embedded in the dense microtubule structure of the mitotic spindle, which spans the region between the segregating chromosome masses (Figure 1), raising the following question: could this network inhibit the recruitment of non-core membranes? In agreement with this possibility, depolymerizing spindle microtubules or "relaxing" the microtubule bundles enables recruitment of non-core components to micronuclei, whereas locking microtubules in place hampers non-core component recruitment. To further test this model, the authors develop a clever approach to generating micronuclei outside the zone of spindle microtubules (Figure 1). Stunningly, such peripheral micronuclei recruit both core and non-core membranes, form a functional nuclear envelope barrier containing transport-competent NPCs, and have reduced DNA damage. Thus, micronuclei formed outside of the vicinity of microtubules are less prone to rupture. Why might spindle microtubules inhibit recruitment of non-core nuclear envelope proteins? The answer may depend on the ultrastructure of the membranes that give rise to the nuclear envelope in an unperturbed mitosis, which remains to be conclusively defined. For example, pioneering experiments using the Xenopus nuclear reconstitution system have shown that vesicle fusion (Macaulay and Forbes, 1996Macaulay C. Forbes D.J. Assembly of the nuclear pore: biochemically distinct steps revealed with NEM, GTP gamma S, and BAPTA.J. Cell Biol. 1996; 132: 5-20Crossref PubMed Scopus (148) Google Scholar) and subsequently membrane tubule capture and spreading at the chromatin surface (Anderson and Hetzer, 2007Anderson D.J. Hetzer M.W. Nuclear envelope formation by chromatin-mediated reorganization of the endoplasmic reticulum.Nat. Cell Biol. 2007; 9: 1160-1166Crossref PubMed Scopus (161) Google Scholar) are key steps in nuclear envelope formation. In contrast, more recent studies in mammalian cell culture models suggest a role for membrane sheets (Lu et al., 2011Lu L. Ladinsky M.S. Kirchhausen T. Formation of the postmitotic nuclear envelope from extended ER cisternae precedes nuclear pore assembly.J. Cell Biol. 2011; 194: 425-440Crossref PubMed Scopus (82) Google Scholar), most likely with small fenestrations (Otsuka et al., 2018Otsuka S. Steyer A.M. Schorb M. Hériché J.-K. Hossain M.J. Sethi S. Kueblbeck M. Schwab Y. Beck M. Ellenberg J. Postmitotic nuclear pore assembly proceeds by radial dilation of small membrane openings.Nat. Struct. Mol. Biol. 2018; 25: 21-28Crossref PubMed Scopus (47) Google Scholar). Taking the findings of Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar into account, it seems reasonable to propose that both tubules and sheets are required for proper nuclear envelope reformation and that these membrane morphologies may define the core and non-core regions, respectively. For example, tubules may be more capable of penetrating the dense spindle microtubules than sheets. Thus, NPCs might be physically excluded from the spindle by virtue of their association with membrane sheets, consistent with their depletion from micronuclei. Interestingly, although micronuclei are ultimately freed of their microtubule "cage" as the cells exit mitosis, they remain unable to establish a normal nuclear envelope. This likely speaks to a critical order of events required to establish a functional nuclear envelope. The altered nuclear envelope composition of micronuclei may also explain why they rupture permanently, apparently refractory to nuclear membrane repair mechanisms driven by the ESCRT machinery (McCullough et al., 2018McCullough J. Frost A. Sundquist W.I. Structures, functions, and dynamics of ESCRT-III/Vps4 membrane remodeling and fission complexes.Annu. Rev. Cell Dev. Biol. 2018; 34: 85-109Crossref PubMed Scopus (124) Google Scholar). Last, other vertebrates have the ability to fuse micronuclei-like organelles (karyomeres) with the primary nucleus (Abrams et al., 2012Abrams E.W. Zhang H. Marlow F.L. Kapp L. Lu S. Mullins M.C. Dynamic assembly of brambleberry mediates nuclear envelope fusion during early development.Cell. 2012; 150: 521-532Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar); mammalian cells appear to have lost this ability, perhaps because they lack an ancient nuclear fusion machinery. Why mammalian cells appear to have neither a strict checkpoint to prevent micronucleus formation nor a salvage mechanism capable of halting their pathology remains an open question. In closing, by interrogating the cause of micronuclei rupture, Liu et al., 2018Liu S. Kwon M. Mannino M. Yang N. Renda F. Khodjakov A. Pellman D. Nuclear envelope assembly defects link mitotic errors to chromothripsis.Nature. 2018; 561: 551-555Crossref PubMed Scopus (154) Google Scholar provide insight into the molecular drivers leading to the exposure of self-DNA to the cytosol. These findings are important not only for understanding processes governing genome instability and the aberrant genetic makeup of cancer cells but also for understanding the fundamental mechanisms governing the reformation of nuclei at the end of mitosis.