Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 47, Pages 39337-39345Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M503320200
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Funding
- NCI NIH HHS [5T32 CA09582, T32 CA009582] Funding Source: Medline
- NIGMS NIH HHS [GM33944] Funding Source: Medline
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Movement of the DNA replication machinery through the double helix induces acute positive supercoiling ahead of the fork and precatenanes behind it. Because topoisomerase I and II create transient single- and double-stranded DNA breaks, respectively, it has been assumed that type I enzymes relax the positive supercoils that precede the replication fork. Conversely, type II enzymes primarily resolve the precatenanes and untangle catenated daughter chromosomes. However, studies on yeast and bacteria suggest that type II topoisomerases may also function ahead of the replication machinery. If this is the case, then positive DNA supercoils should be the preferred relaxation substrate for topoisomerase II alpha, the enzyme isoform involved in replicative processes in humans. Results indicate that human topoisomerase II alpha relaxes positively supercoiled plasmids > 10-fold faster than negatively supercoiled molecules. In contrast, topoisomerase II beta, which is not required for DNA replication, displays no such preference. In addition to its high rates of relaxation, topoisomerase II alpha maintains lower levels of DNA cleavage complexes with positively supercoiled molecules. These properties suggest that human topoisomerase II alpha has the potential to alleviate torsional stress ahead of replication forks in an efficient and safe manner.
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