DNA topoisomerase II and its growing repertoire of biological functions

• Published in: Nature reviews. Cancer Vol. 9; no. 5; pp. 327 - 337
• Main Author: Nitiss, John L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2009; Nature Publishing Group
• Subjects: Adenosine Triphosphate - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis; Catalysis; Chromosome Segregation; Chromosome Structures; DNA Damage; DNA Replication; DNA Topoisomerases, Type II - chemistry; DNA Topoisomerases, Type II - physiology; Genetic aspects; Genetic transcription; Humans; Isomerases; Physiological aspects; Prevention; review-article; Transcription, Genetic; United States
• ISSN: 1474-175X; 1474-1768; 1474-1768
• DOI: 10.1038/nrc2608

The importance of targeting toposimerase II (TOP2) for the treatment of cancer is not a new concept; however, understanding of the biological functions of this enzyme has lagged behind the use of the drugs to target it. This Review discusses what we now know about the functions of TOP2. Key Points Type II topoisomerases change DNA topology by generating transient DNA double strand breaks and are essential for all eukaryotic cells. Mammalian cells have two topoisomerase II (TOP2) isoforms, TOP2α and TOP2β. TOP2α is essential for all cells, and is essential for separating replicated chromosomes. TOP2β is required for normal development, but is dispensable in some cell types. Type II topoisomerases are required for other processes such as transcription, and the precise roles of the two isoforms in these processes are a subject of current studies. Type II topoisomerases use a two gate mechanism for carrying out topological changes in DNA. The enzyme requires ATP hydrolysis for its reaction. ATP hydrolysis is used for for conformational changes of the enzyme, and is not directly involved in DNA breakage or resealing. Crystal structures of several domains of yeast Top2 have provided additional information about how the enzyme carries out its reactions. A recent structure of the breakage reunion domain of yeast Top2 bound to DNA has shown that the enzyme induces a large bend in the DNA that is cleaved by the enzyme. Biological functions of TOP2 isoforms are modulated by a variety of protein–protein interactions. Some of these interactions may affect enzyme activity, stability and localization. TOP2 activity is also modulated by post-translational modification. In addition to phosphorylation, a crucial post-translational modification of TOP2 is sumoylation. Failure to sumoylate TOP2α or to remove the SUMO modification disrupts the ability of TOP2α to separate replicated chromosomes. TOP2β has a key role in the survival of some neural cells. TOP2β is important in transcriptional regulation, and it is likely that TOP2β enzyme activity is specifically required. Some aspects of TOP2 function during the cell cycle are monitored by checkpoints. It has been hypothesized that a major role of checkpoints is to monitor the completion of decatenation. If so, then TOP2-dependent checkpoints may be crucial for normal chromosome segregation and genome stability. DNA topoisomerases are enzymes that disentangle the topological problems that arise in double-stranded DNA. Many of these can be solved by the generation of either single or double strand breaks. However, where there is a clear requirement to alter DNA topology by introducing transient double strand breaks, only DNA topoisomerase II (TOP2) can carry out this reaction. Extensive biochemical and structural studies have provided detailed models of how TOP2 alters DNA structure, and recent molecular studies have greatly expanded knowledge of the biological contexts in which TOP2 functions, such as DNA replication, transcription and chromosome segregation — processes that are essential for preventing tumorigenesis.