The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing

Deweese, Joseph E.; Osheroff, Neil

doi:10.1093/nar/gkn937

Cited by 406 publications

(779 citation statements)

References 142 publications

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“…This dangerous mode of catalysis involves an intermediate (cleavage complex) in which the topoisomerase (Top) is attached either to the 3'-end (Top1), or to the 5'-end (Top2), via a covalent phosphotyrosyl bond. [1][2][3][4] These reversible structures can form persistent protein-linked DNA breaks if they collide with the DNA replication machinery or RNA polymerases. Removal of the covalently linked Top from DNA is required prior to subsequent repair steps.…”

Section: Introductionmentioning

confidence: 99%

TDP1 serine 81 promotes interaction with DNA ligase IIIα and facilitates cell survival following DNA damage

Chiang

Carroll²,

El‐Khamisy

2010

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

TDP1 serine 81 promotes interaction with DNA ligase IIIα and facilitates cell survival following DNA damage

Chiang

Carroll²,

El‐Khamisy

2010

Cell Cycle

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“…Surprisingly, a human enzyme that can preferentially or efficiently cleave DNA 5'-phosphotyrosyl bonds has not been reported, despite the established impact of this type of break on genetic stability and cancer 4,9 . Given that the 3'-tyrosyl DNA phosphodiesterase activity of TTRAP was relatively weak, we wondered whether this enzyme might be a 5'-tyrosyl DNA phosphodiesterase.…”

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confidence: 99%

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

et al. 2014

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Here, we identify such an enzyme in human cells and show that this activity efficiently restores 5'-phosphate termini at DNA double-strand breaks in preparation for DNA ligation. We reveal that this enzyme is TTRAP, a member of the Mg 2+ /Mn 2+ -dependent family of phosphodiesterases, and show that cellular depletion of TTRAP results in increased susceptibility and sensitivity to topoisomerase II-induced DNA double-strand breaks. TTRAP is the first human 5'-tyrosine phosphodiesterase to be identified and we suggest this enzyme additionally be denoted tyrosyl DNA phosphodiesterase-2 (TDP2).In an attempt to identify novel human tyrosyl DNA phosphodiesterase activities, we exploited the hypersensitivity of Saccharomyces cerevisiae tdp1Δ rad1Δ double mutant cells to camptothecin (CPT), a topoisomerase I (Top1) poison that induces single-strand breaks (SSBs) with Top1 covalently linked to the 3'-terminus 3, 10 . This strain lacks not only Tdp1 but also Rad1-Rad10 nuclease, which in yeast provides an alternative (endonucleolytic) pathway for removing Top1 from 3'-termini 11,12 . We transformed this strain with a human cDNA library 3 and screened the resulting population of transformants for cellular resistance to CPT. Of six tdp1Δ rad1Δ transformants displaying wild-type levels of CPT resistance, three harboured cDNA clones encoding TDP1 and three harboured cDNA clones encoding TTRAP (TRAF and TNF receptor-associated protein), a protein of unknown function and a putative member of the Mg 2+ /Mn 2+ -dependent phosphodiesterase super-family, with the DNA repair protein AP endonuclease-1 (APE1) being its closest relative 13,14 (Fig.1a and Supplementary Fig.1).The TDP1 and TTRAP cDNA clones recovered in the genetic screen suppressed the CPT sensitivity of tdp1Δ rad1Δ cells to a similar extent (Fig. 1b & data not shown). Whilst the pACT-TTRAP clones encoded TTRAP protein that lacked eight (pACT-TTRAP-2, pACT-TTRAP-3) or twenty-two (pACT-TTRAP-1) residues from the amino-terminus (data not shown), full-length TTRAP similarly suppressed the CPT sensitivity of tdp1Δ rad1Δ (Fig. 1c, left). In contrast, human APE1 protein failed to suppress this sensitivity, suggesting that ability to complement CPT sensitivity in tdp1Δ rad1Δ cells is not a generic feature of metaldependent phosphodiesterases (Fig. 1c, left). Conversely, whereas human APE1 suppressed the sensitivity of AP endonuclease-defective apn1Δapn2Δ tpp1Δ yeast cells to methyl methanesulphonate (MMS)-induced DNA base damage, human TTRAP did not, suggesting that the impact of TTRAP in these experiments was restricted to topoisomerase-mediated DNA damage ( Fig. 1c, right). TTRAP contains four highly conserved motifs that putatively assign this protein to the metal-dependent phosphodiesterase superfamily (see Fig.1a and Supplementary Fig.1). We thus examined whether mutation of two predicted catalytic residues (Fig.1a; E152 and D262) within two of these motifs impacted on the complementation of CPT sensitivity by TTRAP. Indeed, in contrast to wild-type TTRAP protein, ne...

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“…However, the double helical structure creates topological complications because DNA metabolic processes including replication, transcription, and repair require DNA strand separation (1). These topological complications are resolved by topoisomerases, ubiquitous enzymes found in all phyla that regulate DNA topology and maintain topological homeostasis (2)(3)(4)(5)(6)(7). Topoisomerases are characterized as type I or II based on the number of DNA strands cleaved and dependence on ATP hydrolysis (2,4,5,7).…”

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confidence: 99%

“…Topoisomerases are characterized as type I or II based on the number of DNA strands cleaved and dependence on ATP hydrolysis (2,4,5,7). Topo IIA 3 enzymes share similar core domains and the corresponding catalytic "two-gate" mechanism: passing one segment of duplex DNA (the transfer or T-segment) through a transient double-stranded break in a second segment of DNA (the gate or G-segment) in an ATP-dependent process (5, 6, 8 -10). Catalytically dispensable C-terminal domains (CTDs) are structurally diverse among Topo IIA enzymes, but are important for cellular function as they contain phosphorylation sites and nuclear localization signals (11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Chiral Discrimination and Writhe-dependent Relaxation Mechanism of Human Topoisomerase IIα

Seol

Gentry

Osheroff

et al. 2013

Journal of Biological Chemistry

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Background: Human topoisomerase II␣ unlinks catenated chromosomes and preferentially relaxes positive supercoils. Results: Supercoil chirality, twist density, and tension determine topoisomerase II␣ relaxation rate and processivity. Conclusion: Strand passage rate is determined by the efficiency of transfer segment capture that is modulated by the topoisomerase C-terminal domains. Significance: Single-molecule measurements reveal the mechanism of chiral discrimination and tension dependence of supercoil relaxation by human topoisomerase II␣.

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The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing

Cited by 406 publications

References 142 publications

TDP1 serine 81 promotes interaction with DNA ligase IIIα and facilitates cell survival following DNA damage

TDP1 serine 81 promotes interaction with DNA ligase IIIα and facilitates cell survival following DNA damage

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

Chiral Discrimination and Writhe-dependent Relaxation Mechanism of Human Topoisomerase IIα

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