Trends in Cell Biology

Trends in Cell Biology

Volume 27, Issue 8, August 2017, Pages 546-555
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Review
Bursting the Bubble – Nuclear Envelope Rupture as a Path to Genomic Instability?

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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.

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.

Section snippets

Genomic Instability in Cancer

Genomic instability, defined as an increased rate of alteration in the genome of cells, is one of the hallmarks of cancer and is thought to contribute to cancer progression and resistance to treatment 1, 2. The most common forms of genomic instability in cancer include chromosomal instability (i.e., changes in chromosome number and structure) and genetic mutations/deletions. These changes can lead to inactivation of tumor suppressors or hyperactivation of oncogenes, thereby driving uncontrolled

Controlled NE Breakdown during Mitosis and Interphase

NE breakdown has been studied in extensive detail during mitosis, where the nuclear lamina disassembles in late prophase (prometaphase) in a highly regulated process [13]. In mitosis, disassembly of the NE is mediated by phosphorylation of nuclear pore proteins, lamins, and other NE proteins by protein kinase (PK)C and cyclin dependent kinase (Cdk)1 14, 15. At this stage, the chromosomes are highly condensed, which protects the DNA upon exposure to the cytoplasm. Towards the end of mitosis, in

Mechanically Induced NE Rupture

Recent studies have started to look into the causes that lead to loss of NE integrity in interphase cells apart from the controlled, biochemically mediated NE breakdown events discussed above. These studies demonstrated that physical forces that deform the nucleus can lead to transient NE rupture at sites of local defects in the NE. NE ruptures can be visualized by the escape of GFP tagged with a nuclear localization signal (NLS-GFP) from the nucleus into the cytoplasm, or entry of GFP with a

Changes of NE Composition in Cancer Cells

Abnormal nuclear morphology has been recognized as a tell-tale sign of cancer cells since the early 1800s, and continues to serve as an important diagnostic tool [42]. More recently, it has emerged that many cancers also have altered expression of lamins that can correlate with clinical outcome. For example, skin and ovarian cancer often have higher expression of lamins A/C, whereas leukemia, lymphoma, breast cancer, colon cancer, gastric carcinoma, and some ovarian carcinomas have lower

Consequences of NE Rupture

Nuclear deformation and NE rupture present severe challenges to the integrity of genomic DNA (Figure 2). NE rupture caused by migration through confined environments results in DNA DSBs, which can be detected by staining for the DNA damage repair marker γ-H2AX, or by monitoring accumulation of the fluorescently labeled DNA damage marker 53BP1 7, 10, 12. Live cell imaging reveals 53BP1 accumulation within minutes of NE rupture, both near the NE rupture site but also within the nuclear interior 7

NE Repair

Cells exhibiting NE rupture quickly restore nucleocytoskeletal compartmentalization and remain viable, suggesting that they can efficiently reseal the NE. Nuclear membrane repair requires the ESCRT machinery, including the ESCRT-III proteins CHMP2B, CHMP4B, and CHMP7, as well as the ESCRT-associated AAA ATPase VPS4B 7, 10, 12. These proteins, which are also involved in resealing the reforming NE in late anaphase 16, 17, are rapidly recruited to sites of NE rupture 7, 10, and inhibition of the

Concluding Remarks

Genomic instability has long been recognized as a driver of cancer progression and resistance to intervention, motivating research to better understand the underlying mechanisms. Recent findings suggest that transient loss of NE integrity, resulting from cytoskeletal forces acting on the nucleus, provides a novel mechanism that could contribute to the increased genomic instability of cancer cells. Metastasizing cancer cells that encounter tight interstitial spaces or narrow openings during

Acknowledgments

The authors thank Emily Bell and Philipp Isermann for helpful discussion. The authors apologize to all investigators whose work could not be cited due to space constraints. This work was supported by awards from the National Institutes of Health (R01 HL082792 and U54 CA210184, to J.L.), the Department of Defense Breast Cancer Research Program (Breakthrough Award BC150580, to J.L.), the National Science Foundation (CAREER Award CBET-1254846, to J.L.), and The Netherlands Science Organization

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