Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC)

Sun, Yilun; Saha, Sourav; Wang, Wenjie; Saha, Liton Kumar; Huang, Shar-yin N.; Pommier, ﻿Yves

doi:10.1016/j.dnarep.2020.102837

Cited by 65 publications

(75 citation statements)

References 150 publications

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“…Notably TDP1 and TDP2, Tyrosyl-DNA-Phosphodiesterases 1 and 2, are well-characterised DNA repair proteins that remove the 3 or 5 tyrosyl-DNA adducts with eukaryotic topo I and topo II, respectively [92]. It is interesting to note that, in contrast to what has been hypothesised in bacteria (that there is a protein that can remove gyrase from the DNA and cause lethal breaks), in eukaryotes, this type of protein is involved in repair and not in killing [91,[93][94][95]. This might be because the lethality of topoisomerase poisons in eukaryotes comes from DNA breaks that occur when replication forks collide.…”

Section: Nuclease and Protease Activitymentioning

confidence: 99%

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Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

et al. 2020

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Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.

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Section: Nuclease and Protease Activitymentioning

confidence: 99%

“…In eukaryotes, several proteins are known to remove trapped topoisomerase-DNA complexes [91]. Notably TDP1 and TDP2, Tyrosyl-DNA-Phosphodiesterases 1 and 2, are well-characterised DNA repair proteins that remove the 3 or 5 tyrosyl-DNA adducts with eukaryotic topo I and topo II, respectively [92].…”

Section: Nuclease and Protease Activitymentioning

confidence: 99%

Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

et al. 2020

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“…Both enzymes appear to require proteolysis of the protein component of the DPC before cleaving the phosphotyrosyl bond (21,22). In addition to these specialized nucleases, other nucleolytic enzymes such as MRE11, CtIP, XPF, and XPG can also process DPCs (4,7), although a requirement for prior proteolytic digestion for these enzymes is unclear.…”

Section: Introductionmentioning

confidence: 99%

A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation

et al. 2020

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Topoisomerases form transient covalent DNA cleavage complexes to perform their reactions. Topoisomerase I cleavage complexes (TOP1ccs) are trapped by camptothecin and TOP2ccs by etoposide. Proteolysis of the trapped topoisomerase DNA-protein cross-links (TOP-DPCs) is a key step for some pathways to repair these lesions. We describe a pathway that features a prominent role of the small ubiquitin-like modifier (SUMO) modification for both TOP1- and TOP2-DPC repair. Both undergo rapid and sequential SUMO-2/3 and SUMO-1 modifications in human cells. The SUMO ligase PIAS4 is required for these modifications. RNF4, a SUMO-targeted ubiquitin ligase (STUbL), then ubiquitylates the TOP-DPCs for their subsequent degradation by the proteasome. This pathway is conserved in yeast with Siz1 and Slx5-Slx8, the orthologs of human PIAS4 and RNF4.

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“…Eukaryotic cells carry a specialized enzyme that directly hydrolyzes the Top1-DNA covalent bond -the phosphodiesterase TDP1 (Kawale and Povirk, 2018). Alternatively, Top1ccs can be excised from DNA by several nuclease complexes such as yeast Rad1-Rad10 (human XPF-ERCC1), Slx4-Slx1 (hSLX4-SLX1), Mus81-Mms4 (hMUS81-EME1), Mre11-Rad50-Xrs2 (hMRE11-RAD50-NBS1), and Rad27 (hFEN1) (reviewed in (Sun et al, 2020)). Importantly, large proteins such as full-length Top1 are poor in vitro TDP1 substrates and require at least a partial proteolysis (Debethune et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

Serbyn

Bagdiul

Michel

et al. 2020

Preprint

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Several endogenous metabolites, environmental agents, and therapeutic drugs promote formation of covalent DNA-protein crosslinks (DPCs). Persistent DPCs pose a serious threat to genome integrity and are eliminated by multiple repair pathways. Aberrant Top1 crosslinks to DNA, or Top1ccs, are processed by Tdp1 and Wss1 functioning in parallel pathways in Saccharomyces cerevisiae. It remains obscure how cells choose between these diverse mechanisms of DPC repair. Here we show that several SUMO biogenesis factors -Ulp1, Siz2, Slx5, Slx8 -control repair of Top1cc or an analogous DPC lesion. Genetic analysis reveals that SUMO promotes Top1cc processing in the absence of Tdp1 but has an inhibitory role if cells additionally lack Wss1. In the tdp1D wss1D mutant, the E3 SUMO ligase Siz2 stimulates sumoylation in the vicinity of the DPC, but not SUMO conjugation to Top1. This Siz2-dependent sumoylation delays DPC repair when cells progress through S and G2 phases.Our findings suggest that SUMO tunes available repair pathways to facilitate faithful DPC repair.

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Excision repair of topoisomerase DNA-protein crosslinks (TOP-DPC)

Cited by 65 publications

References 150 publications

Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation

SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways

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