Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

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Abstract

The nuclear envelope safeguards the genetic material inside the nucleus by separating it from the cytoplasm. Until recently, it was assumed that nuclear envelope (NE) breakdown occurs only in a highly controlled fashion during mitosis when the chromatin is condensed and divided between the daughter cells. However, recent studies have demonstrated that adherent and migrating cells exhibit transient NE rupture during interphase caused by compression from cytoskeletal or external forces. NE rupture results in uncontrolled exchange between the nuclear interior and cytoplasm and leads to DNA damage. In this review, we discuss the causes and consequences of NE rupture, and how NE rupture could contribute to genomic instability. Cells exhibit transient NE rupture during migration through confined spaces and actomyosin-based compression, with the incidence of NE rupture increasing with nuclear confinement. NE rupture is preceded by nuclear membrane blebbing from the nuclear lamina, similar to plasma membrane blebbing at the cell cortex. Nuclear membrane blebbing and NE rupture are driven by intranuclear pressure, resulting from perinuclear actomyosin structures that compress the nucleus. At the same time, perinuclear actin structures associated with Arp2/3 and/or the formin FMN2 may promote nuclear transit through constrictions and prevent NE rupture and DNA damage. NE rupture allows the uncontrolled exchange between nuclear and cytoplasmic content, which, together with mechanical deformation of the nucleus, can lead to chromatin protrusion/fragmentation and DNA damage that promote genomic instability. ESCRT-III proteins mediate NE repair, and inhibiting this machinery along with DNA damage repair pathways reduces cell viability after NE rupture.

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Shah, P., Wolf, K., & Lammerding, J. (2017, August 1). Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability? Trends in Cell Biology. Elsevier Ltd. https://doi.org/10.1016/j.tcb.2017.02.008

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