Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2

Schellenberg, M.J.; Appel, C. Denise; Riccio, Amanda A.; Butler, Logan R.; Krahn, J.M.; Liebermann, Jenna A; Cortés‐Ledesma, Felipe; Williams, R. Scott

doi:10.1093/nar/gkaa318

Cited by 15 publications

(11 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Polyubiquitin chains formed by K11 and K63 can also promote proteasomal targeting ( Bedford et al, 2011 ; Kravtsova-Ivantsiv and Ciechanover, 2012 ; Meyer and Rape, 2014 ; Saeki et al, 2009 ). In addition, K27 or K63 polyubiquitin chains may help in docking TDP2 to TOP3Bccs and stimulating TDP2 by engaging its UBA domain as it does for TOP2ccs ( Schellenberg et al, 2020 ). Overall, our results establish the importance of the ubiquitin-proteasomal pathway for the repair of TOP3Bccs in addition to its role for both TOP1ccs and TOP2ccs ( Sun et al, 2020b , 2020c ).…”

Section: Discussionmentioning

confidence: 99%

DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks

et al. 2020

View full text Add to dashboard Cite

SUMMARY The present study demonstrates that topoisomerase 3B (TOP3B) forms both RNA and DNA cleavage complexes (TOP3Bccs) in vivo and reveals a pathway for repairing TOP3Bccs. For inducing and detecting cellular TOP3Bccs, we engineer a “self-trapping” mutant of TOP3B (R338W-TOP3B). Transfection with R338W-TOP3B induces R-loops, genomic damage, and growth defect, which highlights the importance of TOP3Bcc repair mechanisms. To determine how cells repair TOP3Bccs, we deplete tyrosyl-DNA phosphodiesterases (TDP1 and TDP2). TDP2-deficient cells show elevated TOP3Bccs both in DNA and RNA. Conversely, overexpression of TDP2 lowers cellular TOP3Bccs. Using recombinant human TDP2, we demonstrate that TDP2 can process both denatured and proteolyzed TOP3Bccs. We also show that cellular TOP3Bccs are ubiquitinated by the E3 ligase TRIM41 before undergoing proteasomal processing and excision by TDP2.

show abstract

Section: Discussionmentioning

confidence: 99%

DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Recruitment of TDP2 potentially occurs via two different mechanisms depending on the mechanism used to process or remodel the TOP2 adduct. If TOP2 is marked with ubiquitination for subsequent proteasomal degradation, this could recruit TDP2 via it’s N-terminal ubiquitin binding (UBA) domain ( Rao et al, 2016 ; Schellenberg et al, 2020 ). Binding of ubiquitin to the UBA domain of TDP2 does stimulate its phosphodiesterase activity in vitro and TDP2 does bind to a pool of ubiquitinated proteins in vivo , but this pool of ubiquitinated proteins does not appear to include TOP2 ( Rao et al, 2016 ; Schellenberg et al, 2020 ).…”

Section: Repair Of Topoisomerase-mediated Dna Damagementioning

confidence: 99%

“…If TOP2 is marked with ubiquitination for subsequent proteasomal degradation, this could recruit TDP2 via it’s N-terminal ubiquitin binding (UBA) domain ( Rao et al, 2016 ; Schellenberg et al, 2020 ). Binding of ubiquitin to the UBA domain of TDP2 does stimulate its phosphodiesterase activity in vitro and TDP2 does bind to a pool of ubiquitinated proteins in vivo , but this pool of ubiquitinated proteins does not appear to include TOP2 ( Rao et al, 2016 ; Schellenberg et al, 2020 ). Still, there is conflicting evidence for whether deletion of the UBA domain confers hypersensitivity to etoposide depending on the cell-type used, suggesting potential cell-type specific roles for the UBA domain of TDP2 that may or may not be independent of its role in the recruitment of TDP2 to stalled TOP2ccs ( Rao et al, 2016 ; Schellenberg et al, 2020 ).…”

Section: Repair Of Topoisomerase-mediated Dna Damagementioning

confidence: 99%

“…Binding of ubiquitin to the UBA domain of TDP2 does stimulate its phosphodiesterase activity in vitro and TDP2 does bind to a pool of ubiquitinated proteins in vivo , but this pool of ubiquitinated proteins does not appear to include TOP2 ( Rao et al, 2016 ; Schellenberg et al, 2020 ). Still, there is conflicting evidence for whether deletion of the UBA domain confers hypersensitivity to etoposide depending on the cell-type used, suggesting potential cell-type specific roles for the UBA domain of TDP2 that may or may not be independent of its role in the recruitment of TDP2 to stalled TOP2ccs ( Rao et al, 2016 ; Schellenberg et al, 2020 ). Alternatively, SUMOylation of the TOP2 adduct by ZATT to facilitate TOP2 remodeling could recruit TDP2 via its non-canonical SUMO binding (split-SIM) domain ( Schellenberg et al, 2017 ).…”

Section: Repair Of Topoisomerase-mediated Dna Damagementioning

confidence: 99%

See 1 more Smart Citation

Topoisomerase-Mediated DNA Damage in Neurological Disorders

Crewe

Madabhushi

2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

The nervous system is vulnerable to genomic instability and mutations in DNA damage response factors lead to numerous developmental and progressive neurological disorders. Despite this, the sources and mechanisms of DNA damage that are most relevant to the development of neuronal dysfunction are poorly understood. The identification of primarily neurological abnormalities in patients with mutations in TDP1 and TDP2 suggest that topoisomerase-mediated DNA damage could be an important underlying source of neuronal dysfunction. Here we review the potential sources of topoisomerase-induced DNA damage in neurons, describe the cellular mechanisms that have evolved to repair such damage, and discuss the importance of these repair mechanisms for preventing neurological disorders.

show abstract

“…While it was later shown that the TDP2 UBA domain binds K27-and K63-linked polyubiquitin chains, the TDP2 UBA does not bind ubiquitinated TOP2 and the ubiquitinated target required for TDP2dependent repair remains unknown. It is speculated that a ubiquitin-dependent interaction involving the TDP2 UBA domain may induce a conformational change in the TDP2 active site, or may mediate interactions with ubiquitinated histones at DNA damage sites (Kawale and Povirk, 2018;Rao et al, 2016;Schellenberg et al, 2020).…”

Section: Top2 Ubiquitinationmentioning

confidence: 99%

Mechanisms to Repair Stalled Topoisomerase II-DNA Covalent Complexes

2021

View full text Add to dashboard Cite

DNA topoisomerases regulate the topological state of DNA, relaxing DNA supercoils and resolving catenanes and knots that result from biological processes such as transcription and replication. DNA topoisomerase II (TOP2) enzymes achieve this by binding DNA and introducing an enzyme-bridged DNA double-strand break (DSB) where each protomer of the dimeric enzyme is covalently attached to the 5' end of the cleaved DNA via an active site tyrosine phosphodiester linkage. The enzyme then passes a second DNA duplex though the DNA break, before religation and release of the enzyme. However, this activity is potentially hazardous to the cell, as failure to complete religation leads to persistent TOP2 protein-DNA covalent complexes which are cytotoxic. Indeed, this property of topoisomerase has been exploited in cancer therapy in the form of topoisomerase poisons which block the religation stage of the reaction cycle, leading to an accumulation of topoisomerase-DNA adducts. A number of parallel cellular processes have been identified that lead to removal of these covalent TOP2-DNA complexes facilitating repair of the resulting protein-free DSB by standard DNA repair pathways. These pathways presumably arose to repair spontaneous stalled or poisoned TOP2-DNA complexes, but understanding their mechanisms also has implications for cancer therapy, particularly resistance to anti-cancer TOP2 poisons and the genotoxic side effects of these drugs. Here we review recent progress in the understanding of the processing to TOP2 DNA covalent complexes., The basic components and mechanisms plus the additional layer of complexity posed by the post-translational modifications that modulate these pathways. SIGNIFICANCE STATEMENTMultiple pathways have been reported for removal and repair of TOP2-DNA covalent complexes to ensure the timely and efficient repair of TOP2-DNA covalent adducts to protect the genome. Post-translational modifications such as ubiquitination and SUMOylation are involved in the regulation of TOP2-DNA complex repair. Small molecule inhibitors of these post translational modifications may help to improve outcomes of TOP2 poison chemotherapy, for example by increasing TOP2 poison cytotoxicity and reducing genotoxicity, but this remains to be determined.

show abstract

Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2

Cited by 15 publications

References 55 publications

DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks

DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks

Topoisomerase-Mediated DNA Damage in Neurological Disorders

Mechanisms to Repair Stalled Topoisomerase II-DNA Covalent Complexes

Contact Info

Product

Resources

About