The many lives of type IA topoisomerases

Abstract

The double helical structure of genomic DNA is both elegant and functional in that it serves both to protect vulnerable DNA bases and to facilitate DNA replication and compaction. However, these design advantages come at the cost of having to evolve and maintain a cellular machinery that can manipulate a long polymeric molecule that readily becomes topologically entangled whenever it has to open for translation, replication, or repair. If such a machinery fails to eliminate detrimental topological entanglements, utilization of the information stored in the DNA double helix is compromised. As a consequence, the use of Bform DNA as the carrier of genetic information must have co-evolved with a means to manipulate its complex topology. This duty is performed by DNA topoisomerases, which therefore are, unsurprisingly, ubiquitous in all kingdoms of life. In this review, we focus on how DNA topoisomerases catalyze their impressive range of DNA-conjuring tricks, with a particular emphasis on DNA topoisomerase III (TOP3). Once thought to be the most unremarkable of topoisomerases, the many lives of these type IA topoisomerases are now being progressively revealed. This research interest is driven by a realization that their substrate versatility and their ability to engage in intimate collaborations with translocases and other DNA-processing enzymes are far more extensive and impressive than was thought hitherto. This, coupled with the recent associations of TOP3s with developmental and neurological pathologies in humans, is clearly making us reconsider their undeserved reputation as being unexceptional enzymes.

The Long Linker Region of Telomere-Binding Protein TRF2 Is Responsible for Interactions with Lamins

“…Many RNA and DNA helicases resolve RNA/DNA G-quadruplexes that would otherwise pose an obstacle to DNA replication. Topoisomerases TOP1 and TOP3B play a key role in alleviating topological strain during transcription, and their deficiency accumulates R-loops [ 75 ]. TRF2 binds potential G-quadruplex sequences within the telomere, regulates gene expression in some promoter regions of the genome [ 76 ], and, in addition, manages specific topological problems during telomeric replication [ 77 , 78 , 79 ].…”

Diversity and Functions of Type II Topoisomerases

“…Топоизомеразы II разрезают обе цепи в фрагменте ДНК, называемом G-сегментом, и переносят через этот разрыв второй дуплекс -T-сегмент ДНК, гидролизуя при этом две молекулы АТР (рис. 3) [6][7][8]. Эта операция топологически эквивалентна изменению Lk на ±2 [9].…”

Mechanism of Type IA Topoisomerases

“…The C-terminal domains observed in the topoisomerase I of bacteria and the topoisomerase III of higher eukaryotes have evolved to enhance the interactions with nucleic acid substrates and protein–protein interactions using the repeated C-terminal domains and basic amino acid residues. The protein–protein interactions with other cellular proteins are relevant for the physiological functions and regulation of type IA topoisomerase activities [ 38 ]. Basic residues in the C-terminal domains of E. coli topoisomerase I [ 100 ] and the C-terminal tail of M. smegmatis topoisomerase I [ 101 ] have been proposed to interact directly with the β′ subunit of RNA polymerase for the function of topoisomerase I in transcription elongation [ 14 , 102 , 103 ] to suppress hypernegative supercoiling and R-loop accumulation [ 14 , 104 , 105 ].…”

“…Two recent reviews on type IA topoisomerases have discussed the essential functions of bacterial type IA topoisomerase [ 14 ] and the many versatile collaborations engaged by eukaryotic TOP3 to carry out different topological transactions [ 38 ]. This review on the mechanism of type IA topoisomerases will focus more on the results from recent structural, biophysical, biochemical and genetic studies that help us gain a better understanding of how type IA topoisomerases can act as magicians to manipulate the topology of both DNA and RNA, in addition to key remaining questions on the catalytic mechanism.…”