The intracellular and extracellular fate of DNA and chromatin from micronuclei determines their pathogenicity

Circulating cell-free DNA (cfDNA), particularly in blood, is emerging as a critical non-invasive biomarker for the prediction, diagnosis, and monitoring of human diseases. Additionally, cytoplasmic DNA has been implicated in promoting genetic aberrations, genome instability, and inflammation-factors that can contribute to the development of various diseases, including cancer. However, the heterogeneous nature of both intra- and extracellular DNA presents a significant challenge. This review synthesizes current evidence on the origin, composition, and fate of micronuclei (MN) and their derived DNA/chromatin, highlighting their potential as active participants in genomic instability and immune activation. We examine the molecular characteristics of MN, including their formation from acentric fragments, whole chromosomes, or double minutes, and their dynamic intracellular outcomes, such as reintegration, degradation, or extrusion. A major focus is placed on the consequences of micronuclear envelope rupture, including chromothripsis and cGAS-STING-mediated inflammation. We explore the emerging evidence for the extrusion of MN or MN-derived DNA via direct extrusion or packaging in extracellular vesicles, and discuss their implications for cfDNA composition, detection, and biomarker development. The review also underscores the relevance of MN in disease pathogenesis and senescence, and concludes by outlining critical knowledge gaps, particularly concerning the mechanisms of MN clearance, their tissue origin, and their survival and detectability in plasma. In conclusion, by elucidating the mechanistic link between MN biology and cfDNA, we propose that MN-derived DNA and chromatin may serve as informative indicators of genomic instability and disease progression, and offer valuable insights for future diagnostic and therapeutic strategies.