To Break or Not to Break: The Role of TOP2B in Transcription

Abstract

Transcription and its regulation pose challenges related to DNA torsion and supercoiling of the DNA template. RNA polymerase tracking the helical groove of the DNA introduces positive helical torsion and supercoiling upstream and negative torsion and supercoiling behind its direction of travel. This can inhibit transcriptional elongation and other processes essential to transcription. In addition, chromatin remodeling associated with gene activation can generate or be hindered by excess DNA torsional stress in gene regulatory regions. These topological challenges are solved by DNA topoisomerases via a strand-passage reaction which involves transiently breaking and re-joining of one (type I topoisomerases) or both (type II topoisomerases) strands of the phosphodiester backbone. This review will focus on one of the two mammalian type II DNA topoisomerase enzymes, DNA topoisomerase II beta (TOP2B), that have been implicated in correct execution of developmental transcriptional programs and in signal-induced transcription, including transcriptional activation by nuclear hormone ligands. Surprisingly, several lines of evidence indicate that TOP2B-mediated protein-free DNA double-strand breaks are involved in signal-induced transcription. We discuss the possible significance and origins of these DSBs along with a network of protein interaction data supporting a variety of roles for TOP2B in transcriptional regulation.

SMC5 Plays Independent Roles in Congenital Heart Disease and Neurodevelopmental Disability

“…The DSBs that form on promoters of early response genes are mediated by Topoisomerase IIβ (TOP2B) [ 69 , 70 , 71 , 72 ]. Mutations of TOP2B lead to neurodevelopmental disorder and diastolic dysfunction [ 70 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], which are phenotypically similar to when SMC5/6 components are mutated. Research using budding yeast and mammalian cell culture has shown that SMC5/6 and TOP2 physically and functionally interact [ 30 , 80 , 81 ].…”

Bioinformatic Analysis of Topoisomerase IIa Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues

“…consistent with its involvement in replication and mitosis [12][13][14][15][16]. Top2B is more involved in chromatin modulation and remodeling during transcription [12][13][14]16,17]. Type II topoisomerases have been the targets of anticancer drugs for decades because disruption of topoisomerase activity leads to DNA damage and consequently cell death [11,18].…”

Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues

“…Top2A expression fluctuates with the cell cycle and is most highly expressed in S-phase and M-phase consistent with its involvement in replication and mitosis [ 12 , 13 , 14 , 15 , 16 ]. Top2B is more involved in chromatin modulation and remodeling during transcription [ 12 , 13 , 14 , 16 , 17 ]. Type II topoisomerases have been the targets of anticancer drugs for decades because disruption of topoisomerase activity leads to DNA damage and consequently cell death [ 11 , 18 ].…”