Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

Abstract

Micronuclei, small spatially-separated, nucleus-like structures, are a common feature of human cancer cells. There are considerable heterogeneities in the sources, structures and genetic activities of micronuclei. Accumulating evidence suggests that micronuclei and main nuclei represent separate entities with respect to DNA replication, DNA damage sensing and repairing capacity because micronuclei are not monitored by the same checkpoints nor covered by the same nuclear envelope as the main nuclei. Thus, micronuclei are spatially restricted "mutation factories." Several large-scale DNA sequencing and bioinformatics studies over the last few years have revealed that most micronuclei display a mutational signature of chromothripsis immediately after their generation and the underlying molecular mechanisms have been dissected extensively. Clonal expansion of the micronucleated cells is contextdependent and is associated with chromothripsis and several other mutational signatures including extrachromosomal circular DNA, kataegis and chromoanasynthesis. These results suggest what was once thought to be merely a passive indicator of chromosomal instability is now being recognized as a strong mutator phenotype that may drive intratumoral genetic heterogeneity. Herein, we revisit the actionable determinants that contribute to the bursts of mutagenesis in micronuclei and present the growing number of evidence which suggests that micronuclei have distinct shortand long-term mutational and functional effects to cancer genomes. We also pose challenges for studying the long-term effects of micronucleation in the upcoming years.

Novel Targeting of DNA Methyltransferase Activity Inhibits Ewing Sarcoma Cell Proliferation and Enhances Tumor Cell Sensitivity to DNA Damaging Drugs by Activating the DNA Damage Response

“…We also evaluated the impact of MC3343 on genomic instability in four EWS cell lines. Control and treated cells were cultured for 6 to 24 hours, and the impact on genome stability monitored by evaluating micronuclei, a well-recognized marker of genomic instability ( 43 ) ( Figures 4A, B ). This effect was better represented in p53 mutated TC-71 and A-673 cells than in p53wt LA-P35 and PDX-EW#4-C cells (p< 0.0001 Student’s t test).…”

Effects of dietary restriction on genome stability are sex and feeding regimen dependent

“…Recent evidence supported that MN is also a strong mutator phenotype that can drive genetic heterogeneity through catastrophic events such as chromothripsis (a novel form of GIN in cancer cells) in the MNed chromosome. 35 Besides, the pres-ence of MN is linked to cellular senescence and apoptosis. 34 For example, MN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway, which is a driving force for cellular senescence and cancer.…”

Extrachromosomal Circular DNA: A New Target in Cancer

“…In recent years, research on the mechanism of eccDNA formation has tended to focus on the chromothripsis model ( 63 – 65 ). Vogt et al.…”