Figure 1 -The proximity of mitochondria to micronuclei drives micronuclear membrane rupture through mitochondria-derived reactive oxygen species (ROS). ROS inhibit micronuclear export, leading to the excessive accumulation of CHMP7, a scaffolding protein associated with the nuclear membrane repair complex ESCRT-III. ROS-dependent cysteine oxidation promotes CHMP7 self-aggregation and its aberrant binding to the membrane protein LEMD2, causing micronuclear collapse. [Figure created with BioRender.com]
Chromosomal instability, a key feature of aggressive cancers, often leads to the formation of micronuclei—small, extranuclear bodies containing chromosomes or chromosome fragments. Unlike the main nucleus, micronuclei have a fragile membrane prone to rupture, leading to catastrophic consequences for the cell.
What Are Micronuclei? Micronuclei form during cell division (mitosis) when chromosomes fail to be included in the daughter nuclei. These micronuclei are much smaller and have an abnormal nuclear envelope with defective nuclear pores and reduced levels of lamin B1. This fragile structure makes them susceptible to rupture.
The Consequences of Micronuclear Rupture: When the membrane of a micronucleus ruptures, its DNA is released into the cytosol—the fluid inside the cell. This DNA is recognized as foreign by the cell, triggering a DNA damage response that leads to genomic instability—a driving force behind cancer development. The rupture also activates the cGAS-STING pathway, a component of the innate immune system, leading to chronic inflammation that promotes tumor growth, metastasis, and immune evasion.
The Role of Oxidative Stress: Recent research has identified a novel link between oxidative stress, particularly reactive oxygen species (ROS), and micronuclear collapse. ROS disrupts the function of the nuclear membrane repair complex, ESCRT-III, specifically by altering the behavior of the CHMP7 protein. Elevated ROS levels lead to CHMP7 aggregation in micronuclei, where it binds abnormally to the inner nuclear membrane protein LEMD2, causing membrane deformation and collapse. ROS also recruits the autophagy-related protein p62, which degrades other ESCRT-III components, further preventing membrane repair.
Clinical Implications: These findings highlight the connection between oxidative stress conditions, such as hypoxia (low oxygen levels), and the genetic and epigenetic alterations that drive cancer progression. The studies showed that hypoxia-induced ROS led to micronuclear rupture and chromosomal rearrangements in human tumors. This mechanism is particularly relevant in hypoxic regions of cancers like head and neck and ovarian tumors.
Conclusion: The collapse of micronuclei is more than a mere cellular mishap; it is a critical process that drives cancer progression by promoting chromosomal instability and inflammation. Understanding the role of oxidative damage in this process opens new avenues for therapeutic intervention, offering potential strategies to target the underlying causes of genomic instability in cancer.
References: Maddaluno, M., & Settembre, C. (2024). Micronuclear collapse mechanisms in cancer: Oxidative damage triggers micronuclear membrane rupture and defective repair. Science, 385(6712), 930-931. https://doi.org/10.1126/science.adr7417
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