Micronuclei and Genome Chaos: Changing the System Inheritance

Abstract

Micronuclei research has regained its popularity due to the realization that genome chaos, a rapid and massive genome re-organization under stress, represents a major common mechanism for punctuated cancer evolution. The molecular link between micronuclei and chromothripsis (one subtype of genome chaos which has a selection advantage due to the limited local scales of chromosome re-organization), has recently become a hot topic, especially since the link between micronuclei and immune activation has been identified. Many diverse molecular mechanisms have been illustrated to explain the causative relationship between micronuclei and genome chaos. However, the newly revealed complexity also causes confusion regarding the common mechanisms of micronuclei and their impact on genomic systems. To make sense of these diverse and even conflicting observations, the genome theory is applied in order to explain a stress mediated common mechanism of the generation of micronuclei and their contribution to somatic evolution by altering the original set of information and system inheritance in which cellular selection functions. To achieve this goal, a history and a current new trend of micronuclei research is briefly reviewed, followed by a review of arising key issues essential in advancing the field, including the re-classification of micronuclei and how to unify diverse molecular characterizations. The mechanistic understanding of micronuclei and their biological function is re-examined based on the genome theory. Specifically, such analyses propose that micronuclei represent an effective way in changing the system inheritance by altering the coding of chromosomes, which belongs to the common evolutionary mechanism of cellular adaptation and its trade-off. Further studies of the role of micronuclei in disease need to be focused on the behavior of the adaptive system rather than specific molecular mechanisms that generate micronuclei. This new model can clarify issues important to stress induced micronuclei and genome instability, the formation and maintenance of genomic information, and cellular evolution essential in many common and complex diseases such as cancer.

Somatic Genomic Mosaicism in Multiple Myeloma

“…In fact, chromosomal profiles have extensively been associated with prognosis in MM, based on specific translocation, hyperdiploidy, chromosomal amplification/deletion, and chromosomal copy number abnormalities (Garcia-Sanz et al, 1995;Avet-Loiseau et al, 2007, 2009Walker et al, 2010;Shah et al, 2018). By converting DNA sequence data into aneuploidy data, we showed that the status of aneuploidy can suggest clinical MM outcomes (Ye et al, 2019a). (2) Cancer often represents an evolutionary trade-off of cellular variation-mediated function.…”

“…However, they have often been ignored due to the popularity of gene-centric concepts. Changing the karyotype coding is a hallmark of somatic and organismal macroevolution (Heng, 2019;Ye et al, 2019a).…”

Chromosome Instability; Implications in Cancer Development, Progression, and Clinical Outcomes

“…Single cell approaches have also been developed to quantify and compare surrogate markers of CIN (e.g., CIN-associated phenotypes), including micronucleus formation [28,29] and changes in nuclear areas [29] or human artificial chromosomes [30]. Conceptually, micronuclei are extra nuclear bodies that are found outside the primary nucleus and are hallmarks of CIN that typically arise due to chromosome missegregation events [31][32][33], while changes in nuclear areas and human artificial chromosomes are associated with small and large (i.e., ploidy) scale changes in DNA content, respectively [30,[34][35][36][37][38]. These approaches typically involve quantitative imaging microscopy or flow cytometry that are each capable of rapidly assessing CIN-associated phenotypes in hundreds-to-thousands of cells [28,29,39].…”

Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation

“…One final consideration stems from the lack of evidence for RNA-protein 5′ phosphotyrosyl bonds similar to those linking VPg to the viral RNA in uninfected human cells and how the presence of DNA linked to protein by 5′ phosphotyrosyl bonds in the cytoplasm might be a putative signal for the activation of innate immune pathways [65]. It is conceivable that picornaviruses have evolved to ensure that this type of linkage is not recognized by the host via hydrolysis of VPg from the RNA immediately upon infection and during the early stages of replication.…”