Abstract
DNA topoisomerase II (TOP2) plays a critical role in many processes such as replication and transcription, where it resolves DNA structures and relieves torsional stress. Recent evidence demonstrated the association of TOP2 with topologically associated domains (TAD) boundaries and CCCTC-binding factor (CTCF) binding sites. At these sites, TOP2 promotes interactions between enhancers and gene promoters, and relieves torsional stress that accumulates at these physical barriers. Interestingly, in executing its enzymatic function, TOP2 contributes to DNA fragility through re-ligation failure, which results in persistent DNA breaks when unrepaired or illegitimately repaired. Here, we discuss the biological processes for which TOP2 is required and the steps at which it can introduce DNA breaks. We describe the repair processes that follow removal of TOP2 adducts and the resultant broken DNA ends, and present how these processes can contribute to disease-associated mutations. Furthermore, we examine the involvement of TOP2-induced breaks in the formation of oncogenic translocations of leukemia and papillary thyroid cancer, as well as the role of TOP2 and proteins which repair TOP2 adducts in other diseases. The participation of TOP2 in generating persistent DNA breaks and leading to diseases such as cancer, could have an impact on disease treatment and prevention.
Highlights
Topoisomerases relieve supercoiling in a sequence-independent manner by transiently cutting the DNA, passing the DNA strand through the break, and re-ligating the strand(s) [1,2]
This study suggests that the surrounding AT-rich region created a chromatin structure that required TOP2B to relieve repression of gene expression [63]
Following treatment with the TOP2 poison etoposide, coverage-normalized cross correlation (CNCC) revealed a global pattern of 30 overhangs, indicating 50 to 30 resection activity likely resulting from repair of TOP2 cleavage complex (TOP2cc)
Summary
Topoisomerases relieve supercoiling in a sequence-independent manner by transiently cutting the DNA, passing the DNA strand through the break, and re-ligating the strand(s) [1,2]. The two major groups/types of topoisomerases are type I and type II, with type I enzymes generating single-stranded breaks and type II enzymes generating double-stranded DNA breaks (DSBs) [1,2]. Catalytic inhibitors of TOP2, such as merbarone [5,6], prevent the initial TOP2 cleavage of DNA, while TOP2 poisons prevent the re-ligation by stabilizing the TOP2cc state. By stabilizing TOP2ccs, TOP2 poisons promote the persistence of DSBs generated in the process [17]. The consequences of TOP2-induced DSBs are dependent on where the breaks are generated, both endogenously and in response to external stressors, and how the TOP2ccs are removed and repaired
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