Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA

@article{Morimoto2019TypeID,
  title={Type II DNA Topoisomerases Cause Spontaneous Double-Strand Breaks in Genomic DNA},
  author={Suguru Morimoto and Masataka Tsuda and Heeyoun Bunch and Hiroyuki Sasanuma and Caroline A. Austin and Shunichi Takeda},
  journal={Genes},
  year={2019},
  volume={10}
}
Type II DNA topoisomerase enzymes (TOP2) catalyze topological changes by strand passage reactions. They involve passing one intact double stranded DNA duplex through a transient enzyme-bridged break in another (gated helix) followed by ligation of the break by TOP2. A TOP2 poison, etoposide blocks TOP2 catalysis at the ligation step of the enzyme-bridged break, increasing the number of stable TOP2 cleavage complexes (TOP2ccs). Remarkably, such pathological TOP2ccs are formed during the normal… Expand
Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC).
TLDR
The purpose of this review is to summarize the current understanding of how the cell excises TOP-DPC and why, when and where the cell recruits one specific mechanism for repairing topoisomerase-mediated DNA damage, acquiring resistance to therapeutic topoisomersase inhibitors and avoiding genomic instability, cancers and neurodegenerative diseases. Expand
Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase 1 DNA-protein crosslinks and 3'-blocking lesions in the absence of tyrosyl-DNA phosphodiesterase 1 (TDP1).
TLDR
An assay system to estimate repair kinetics of TOP1cc separately in the first and second steps, using monoclonal antibodies against the TOP1 protein and the TOP 1 catalytic site peptide-DNA complex, confirmed the roles of TDP2 in the repair of 3'-blocking lesions. Expand
Debulking of topoisomerase DNA-protein crosslinks (TOP-DPC) by the proteasome, non-proteasomal and non-proteolytic pathways.
TLDR
This review focuses on current knowledge of the protease pathways for debulking TOP-DPC and highlighting recent advances in understanding the mechanisms regulating the proteolytic repair pathways, including metalloprotease SPRTN/WSS1. Expand
BRCA1-BARD1 regulates transcription through modulating topoisomerase IIβ
TLDR
A novel role is presented for the BRCA1-BARD1 complex in regulating the transcription of serum-inducible genes and the stability of topoisomerase IIβ in transcription in humans. Expand
The Epstein-Barr virus ubiquitin deconjugase BPLF1 regulates the activity of Topoisomerase II during virus replication
TLDR
Findings highlight a previously unrecognized function of BPLF1 in promoting non-proteolytic pathways for TOP2cc debulking that favor cell survival and virus production. Expand
TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands
TLDR
Physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs, as shown in Figure 1. Expand
Targeting DNA Damage Response in Prostate and Breast Cancer
TLDR
The combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation, and preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Expand
Programmed DNA Damage and Physiological DSBs: Mapping, Biological Significance and Perturbations in Disease States
TLDR
What is known about DNA damage in its physiological context is summarized and the advancements of the past several years are examined, which have made an impact on the study of genome landscape and its organization. Expand
Functional regulation of the structure-specific endonuclease FEN1 by the human cytomegalovirus protein IE1 suggests a role for the re-initiation of stalled viral replication forks
TLDR
The results indicate that FEN1 is required for the formation of DSBs during HCMV infection suggesting that IE1 acts as viral activator of F EN1 in order to re-initiate stalled replication forks. Expand
25.2: DNA Mutations, Damage, and Repair
    Mutations are random changes that occur within the sequence of bases in DNA. They can be large scale, altering the structure of the chromosomes, or small scale where they only alter a few or even aExpand
    ...
    1
    2
    3
    ...

    References

    SHOWING 1-10 OF 136 REFERENCES
    Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes
    TLDR
    It is reported that TDP2 alone does not remove TOP2-DNA complexes from genomic DNA in vitro and in cells and that depletion of TDP1 in cells does not slow the removal of Topoisomerase II complexes. Expand
    Topoisomerase I‐mediated cleavage at unrepaired ribonucleotides generates DNA double‐strand breaks
    TLDR
    Genetic and biochemical evidence is provided that DNA double‐strand breaks (DSBs) can be directly generated by Top1 at sites of genomic ribonucleotides and biochemically that irreversible DSBs are generated by subsequent Top1 cleavage on the opposite strand from the Top1‐induced DNA nicks at ribon DNA sites. Expand
    MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA
    TLDR
    Basal topoisomerase II complex levels were very high in A-TLD cells lacking full-length wild type MRE11, suggesting that MRE 11 facilitates the processing of topoisomersase complexes that arise as part of normal cellular metabolism. Expand
    Roles of eukaryotic topoisomerases in transcription, replication and genomic stability
    TLDR
    The roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability are reviewed, and how deregulation of top Loisomerases can cause neurodegenerative diseases, immune disorders and cancer are discussed. Expand
    TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1
    TLDR
    It is suggested that Tdp1 and Tdp2 fulfil overlapping roles following Top1-induced DNA damage, but not following Top2-inducedDNA damage, in vivo. Expand
    TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
    TLDR
    It is shown that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation ‘hotspot’, MLL, and the importance of T DP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability is demonstrated. Expand
    ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links
    TLDR
    The findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc, a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. Expand
    The Roles of DNA Topoisomerase IIβ in Transcription
    • R. Madabhushi
    • Medicine, Biology
    • International journal of molecular sciences
    • 2018
    TLDR
    This review begins with a summary of the initial studies surrounding the discovery and characterization of Topo IIβ and then focuses on the insights gained from more recent studies that have elaborated important functions for Topa IIβ in transcriptional regulation. Expand
    Intrinsic intermolecular DNA ligation activity of eukaryotic topoisomerase II. Potential roles in recombination.
    TLDR
    It is demonstrated that the type II enzyme has an intrinsic ability to mediate illegitimate DNA recombination in vitro and suggests possible roles for topoisomerase II in nucleic acid recombinations in vivo. Expand
    A Topoisomerase IIß-Mediated dsDNA Break Required for Regulated Transcription
    TLDR
    It is reported that the signal-dependent activation of gene transcription by nuclear receptors and other classes of DNA binding transcription factors, including activating protein 1, requires DNA topoisomerase IIβ-dependent, transient, site-specific dsDNA break formation. Expand
    ...
    1
    2
    3
    4
    5
    ...