Repair of Topoisomerase II-Mediated DNA Damage: Fixing DNA Damage Arising from a Protein Covalently Trapped on DNA

Nitiss, John L.; Soans, Eroica; Berk, Jeffrey; Seth, Aman; Mishina, Margarita; Nitiss, Karin C.

doi:10.1007/978-1-4614-0323-4_18

Cited by 2 publications

(6 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eukaryotic cells harbor two different tyrosyl DNA-phosphodiesterases, TDP1 and TDP2. Even though both hydrolyze topoisomerase tyrosyl-DNA phosphodiester bonds, they show no sequence homology or structural similarity (Bahmed et al, 2010;Cortes Ledesma et al, 2009;Kawale and Povirk, 2018;Nitiss and Nitiss, 2013;Nitiss et al, 2012;Pommier et al, 2014). By contrast to TDP1 (Cortes Ledesma et al, 2009;Yang et al, 1996), which belongs to the phospholipase D family (Interthal et al, 2001)], TDP2 belongs to the Mg 2+ /Mn 2+ -dependent family of endonucleases and exhibits high sequence similarities with the human DNA repair enzyme apurinic/apyrimidinic endonuclease-1 (APE1) (Cortes Ledesma et al, 2009;Gao et al, 2012;Nitiss and Nitiss, 2013;Pommier et al, 2014;Rodrigues-Lima et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Saha

Huang

et al. 2020

Preprint

View full text Add to dashboard Cite

2 HIGHLIGHTS• Method for in vivo detection of TOP3B cleavage complexes (TOP3Bccs) formed both in DNA and RNA, using a religation defective "self-trapping" R338W TOP3B mutant. • First evidence that TDP2 excises TOPccs produced by a type IA topoisomerase. • TDP2 processes both RNA and DNA TOP3Bccs following their ubiquitylation and proteasomal degradation inside cell. • TRIM41 is the first reported E3 ubiquitin ligase for TOP3Bcc ubiquitylation and proteasomal degradation. SUMMARY (150 words)Genetic inactivation of TOP3B is linked with schizophrenia, autism, intellectual disability and cancer. The present study demonstrates that in vivo TOP3B forms both RNA and DNA cleavage complexes (TOP3Bccs) and reveals a pathway for repairing TOP3Bccs. For detecting cellular TOP3Bccs, we engineered a "self-trapping" mutant of TOP3B (R338W TOP3B) and to determine how human cells repair TOP3Bccs, we depleted tyrosyl-DNA phosphodiesterases (TDP1 and TDP2). TDP2-deficient cells produced elevated TOP3Bccs both in DNA and RNA. Conversely, overexpression of TDP2 lowered cellular TOP3Bccs. Using recombinant human TDP2, we demonstrate that TDP2 cannot excise the native form of TOP3Bccs. Hypothesizing that TDP2 cannot access phosphotyrosyl linkage unless TOP3B is either proteolyzed or denatured, we found that cellular TOP3Bccs are ubiquitinated by the E3 Ubiquitin Ligase TRIM41 before undergoing proteasomal degradation and excision by TDP2.3

show abstract

Section: Discussionmentioning

confidence: 99%

Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Saha

Huang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Homologous recombination (HR) is also important for the repair of Top2-induced DNA damage, as demonstrated genetically both in yeast and DT40 models [131,139,140]. The two pathways probably work in parallel with the HR pathway downstream from the endonuclease pathway(s) (Fig.…”

Section: Tyrosyl-dna Phosphodiesterase 2 (Tdp2)mentioning

confidence: 99%

“…One reason is that yeast does not appear to use TDP2 pathways for repairing aborted Top2cc, and its primary pathways rely on endonucleases [140] (see Fig. 2B).…”

Section: Tdp Inhibitorsmentioning

confidence: 99%

“…For Top1, they include XPF-ERCC1 [29,55], Mre11-Rad50-Nibrin/Nbs1 (MRN) [148], SLX4 [161] and CtIP [149,150,162]. For Top2, they include MRN and CtIP [reviewed in [140]]. Double-arrows and orange text indicate the pathways that finalize DNA repair.…”

Section: Figmentioning

confidence: 99%

“…In the case of Top1 (A), homologous recombination (HR including the BRCA proteins) is critical for repairing the double-strand ends generated by replication run-off [102]. For Top2 (B), end-joining (EJ) with Ku and ligase IV are essential downstream from TDP2 [27,131,132] whereas HR is linked to the endonuclease pathway [140]. …”

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

View full text Add to dashboard Cite

TDP1 and TDP2 were discovered and named based on the fact they process 3′- and 5′-DNA ends by excising irreversible protein tyrosyl-DNA complexes involving topoisomerases I and II, respectively. Yet, both enzymes have an extended spectrum of activities. TDP1 not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3′-phosphoglycolates and alkylation damage-induced DNA breaks, and excises chain terminating anticancer and antiviral nucleosides in the nucleus and mitochondria. The repair function of TDP2 is devoted to the excision of topoisomerase II- and potentially topoisomerases III-DNA adducts. TDP2 is also essential for the life cycle of picornaviruses (important human and bovine pathogens) as it unlinks VPg proteins from the 5′-end of the viral RNA genome. Moreover, TDP2 has been involved in signal transduction (under the former names of TTRAP or EAPII). The DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway. By contrast, TDP2 repair functions are coordinated with Ku and ligase IV in the non-homologous end joining pathway (NHEJ). This article summarizes and compares the biochemistry, functions, and post-translational regulation of TDP1 and TDP2, as well as the relevance of TDP1 and TDP2 as determinants of response to anticancer agents. We discuss the rationale for developing TDP inhibitors for combinations with topoisomerase inhibitors (topotecan, irinotecan, doxorubicin, etoposide, mitoxantrone) and DNA damaging agents (temozolomide, bleomycin, cytarabine, and ionizing radiation), and as novel antiviral agents.

show abstract

Repair of Topoisomerase II-Mediated DNA Damage: Fixing DNA Damage Arising from a Protein Covalently Trapped on DNA

Cited by 2 publications

References 99 publications

Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-linked RNA and DNA Breaks

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

Contact Info

Product

Resources

About