miRNA dysregulation is an emerging modulator of genomic instability

Abstract

Genomic instability consists of a range of genetic alterations within the genome that contributes to tumor heterogeneity and drug resistance. It is a well-established characteristic of most cancer cells. Genome instability induction results from defects in DNA damage surveillance mechanisms, mitotic checkpoints and DNA repair machinery. Accumulation of genetic alterations ultimately sets cells towards malignant transformation. Recent studies suggest that miRNAs are key players in mediating genome instability. miRNAs are a class of small RNAs expressed in most somatic tissues and are part of the epigenome. Importantly, in many cancers, miRNA expression is dysregulated. Consequently, this review examines the role of miRNA dysregulation as a causal step for induction of genome instability and subsequent carcinogenesis. We focus specifically on mechanistic studies assessing miRNA(s) and specific subtypes of genome instability or known modes of genome instability. In addition, we provide insight on the existing knowledge gaps within the field and possible ways to address them.

Keywords: Chromosomal instability; DNA repair; Genomic instability; miRNA.

Figure 1.

Summary of literature search strategy depicting screening procedures and exclusion criteria.

Figure 2.

Simplified schematic representation of mechanisms leading to various forms of CIN (only the most common forms of CIN are shown). Numerical and structural chromosomal instability arise from improper segregation of chromosome(s) during mitosis. Numerical and structural alterations predispose chromosomes to subsequent chromosomal alterations, increasing instability.

Figure 3.

Simplified schematic representation summarizing the causal relationships by which miRNA dysregulation can lead to accumulation of heightened DNA damage. The figure includes only those forms of DNA damage, DDR and DNA repair pathways whose induction/perpetuation have been causally linked with at least one dysregulated miRNA expression (Mismatch Repair, Non-Homologous End Joining, Homologous Recombination and Interstrand Crosslink Repair). “(?)” denotes that so far no information is available for the miRNA modulation of the particular DNA damage pathway.

Figure 4.

Simplified schematic representation summarizing the causal relationships by which miRNA dysregulation leads to mitotic disruption. The figure depicts how miRNA(s) disrupt prometaphase to metaphase transition and cause dysregulation of Spindle Assembly Checkpoint by targeting components of the Mitotic Checkpoint Complex leading to improper chromatid segregation and ultimately aneuploidy. Please note that no data are currently available causally linking miRNA dysregulation to disruption of other cell cycle stages.