Nuclear envelope rupture and repair during cancer cell migration
By C. Denais, R. Gilbert, Philipp Isermann, Alexandra L. McGregor, Mariska te Lindert, B. Weigelin, P. Davidson, Peter Friedl, Katarina Wolf, J. Lammerding. Science, 2016
1,198 citations recorded by the source corpus.
Repairing tears in the nuclear envelope The nuclear envelope segregates genomic DNA from the cytoplasm and regulates protein trafficking between the cytosol and the nucleus. Maintaining nuclear envelope integrity during interphase is considered crucial. However, Raab et al. and Denais et al. show that migrating immune and cancer cells experience frequent and transitory nuclear envelope ruptures when they move through tight spaces (see the Perspective by Burke). The nuclear envelope reseals rapidly during interphase, assisted by components of the ESCRT III membrane-remodeling machinery. Science, this issue pp. 359 and 353; see also p. 295 When cells migrate, they stress their nuclear envelopes and need to guard against leakage of the nuclear contents. [Also see Perspective by Burke] During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/37a0a12ded06e555ce8be7a55c4ea26f916cbb78
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Citations in the corpus
- Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear Pores. (2017, neutral): “Importantly, YAP nuclear translocation is not due to the breakage of the nucleo-cytoplasmic barrier under force, as occurs under very high nuclear deformations (Denais et al., 2016; Raab et al., 2016; Skau et al., 2016).”
- cGAS in action: Expanding roles in immunity and inflammation (2019, background): “For example, acute nuclear membrane damage such as that occurring during cell migration is perceived by cGAS, but rapid sealing of nuclear perforations through the ESCRTmachinery possibly prevents the generation of an inflammatory signal (63, 64).”
- The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “It was recently reported that NE of the nucleus can be rapidly repaired by the endosomal sorting complexes required for transport III (ESC RT-III) complex (Denais et al., 2016; Raab et al., 2016), and this mechanism may provide similar protection to NEs of micronuclei.”