Roles of Topoisomerases in Heterochromatin, Aging, and Diseases

Abstract

Heterochromatin is a transcriptionally repressive chromatin architecture that has a low abundance of genes but an enrichment of transposons. Defects in heterochromatin can cause the de-repression of genes and transposons, leading to deleterious physiological changes such as aging, cancer, and neurological disorders. While the roles of topoisomerases in many DNA-based processes have been investigated and reviewed, their roles in heterochromatin formation and function are only beginning to be understood. In this review, we discuss recent findings on how topoisomerases can promote heterochromatin organization and impact the transcription of genes and transposons. We will focus on two topoisomerases: Top2α, which catenates and decatenates double-stranded DNA, and Top3β, which can change the topology of not only DNA, but also RNA. Both enzymes are required for normal heterochromatin formation and function, as the inactivation of either protein by genetic mutations or chemical inhibitors can result in defective heterochromatin formation and the de-silencing of transposons. These defects may contribute to the shortened lifespan and neurological disorders observed in individuals carrying mutations of Top3β. We propose that topological stress may be generated in both DNA and RNA during heterochromatin formation and function, which depend on multiple topoisomerases to resolve.

Keywords: Top2; Top3β; aging; disease; heterochromatin; topoisomerase; transposon.

Figure 1

Top2α and the BAF complex cooperate to facilitate access to facultative heterochromatin. A model illustrating how Top2α and the BAF complex may work together to facilitate access to facultative heterochromatin. The BAF complex uses its ATP-dependent chromatin remodeling activity to disrupt the Polycomb group (PcG) complex containing facultative heterochromatin. Top2α is recruited in the early stage of chromatin remodeling to resolve the topological stress produced by the BAF complex, possibly using its DNA decatenation activity. This model is based on findings in the paper of Miller et al. (Nat. Struct. Mol. Biol., 2017).

Figure 2

Top2α promotes the formation of facultative heterochromatin. A model illustrating how Top2α may facilitate the formation of facultative heterochromatin. Facultative heterochromatin may consist of DNA that is more catenated than that in the accessible chromatin. Top2α may catalyze DNA catenation during the formation of facultative heterochromatin from accessible chromatin. This model is based on the findings in a previous paper (Miller et al., Nat. Struct. Mol. Biol., 2017).

Figure 3

Top3β is a dual-activity topoisomerase that can act on both DNA and RNA, including RNAi-guided heterochromatin formation. (A) A cartoon illustrating that Top3β forms a complex with TDRD3, which interacts with FMRP. This complex can stimulate DNA transcription, mRNA translation, and siRNA-guided heterochromatin formation. (B) A cartoon illustrates human and Drosophila Top3β–TDRD3 complexes. In the latter species, Top3β–TDRD3 stably associates with the RNA-induced silencing complex (RISC) complex containing Argonaut 2 (AGO2), p68, FMRP, and VIG. It remains to be determined if mammalian Top3b–TDRD3 can also interact with RISC. (C) A model illustrates how Top3β may function during siRNA-guided heterochromatin formation. The model postulates that the unwinding of nascent transcript by p68 may generate entangled or supercoiled RNA that requires topoisomerase activity to resolve. Unwound RNAs by Top3β and p68 become more accessible for targeting by RISC to silence transposable elements (TE) as well as recruiting heterochromatin factors histone methyltransferase (HMT) and heterochromatin protein 1 (HP1).