SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair

Hudson, Jessica J. R.; Chiang, Shih‐Chieh; Wells, Owen; Rookyard, Chris; El‐Khamisy, Sherif F.

doi:10.1038/ncomms1739

Cited by 79 publications

(80 citation statements)

References 55 publications

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“…It has been suggested that the TDP1 N-terminal domain mediates interactions with DNA repair proteins (28, 48–50). Deletion of the N-terminal domain of TDP1 produced the catalytically active TDP1-ΔN (Fig.…”

Section: Resultsmentioning

confidence: 99%

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

Heo

Summerlin

et al. 2015

DNA Repair

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The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. In tumor cells, the ability to repair DSBs predicts response to radiation and many cytotoxic anti-cancer drugs. DSB repair pathways include homologous recombination and non-homologous end joining (NHEJ). NHEJ is a template-independent mechanism, yet many NHEJ repair products carry limited genetic changes, which suggests that NHEJ includes mechanisms to minimize error. Proteins required for mammalian NHEJ include Ku70/80, the DNA-dependent protein kinase (DNA-PKcs), XLF/Cernunnos and the XRCC4:DNA ligase IV complex. NHEJ also utilizes accessory proteins that include DNA polymerases, nucleases, and other end-processing factors. In yeast, mutations of tyrosyl-DNA phosphodiesterase (TDP1) reduced NHEJ fidelity. TDP1 plays an important role in repair of topoisomerase-mediated DNA damage and 3′-blocking DNA lesions, and mutation of the human TDP1 gene results in an inherited human neuropathy termed SCAN1. We found that human TDP1 stimulated DNA binding by XLF and physically interacted with XLF to form TDP1:XLF:DNA complexes. TDP1:XLF interactions preferentially stimulated TDP1 activity on dsDNA as compared to ssDNA. TDP1 also promoted DNA binding by Ku70/80 and stimulated DNA-PK activity. Because Ku70/80 and XLF are the first factors recruited to the DSB at the onset of NHEJ, our data suggest a role for TDP1 during the early stages of mammalian NHEJ.

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Section: Resultsmentioning

confidence: 99%

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

Heo

Summerlin

et al. 2015

DNA Repair

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“…4A) promotes DNA repair and TDP1 accumulation at Top1cc-induced and UV-laser-induced DNA damage sites [105]. SUMOylation is catalyzed in a three-step process by E1, E2, and E3 enzymes followed by desumoylation by proteases specifically recognizing SUMO conjugates [106,107].…”

Section: Tyrosyl-dna Phosphodiesterase 1 (Tdp1)mentioning

confidence: 99%

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

et al. 2014

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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.

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“…Upon exposure to H 2 O 2 , 1000-fold more SSBs are induced in nDNA as compared with DSBs (Caldecott 2008). SSBs can also arise as a result of erroneous or abortive activity of DNA topoisomerase 1 (Hudson et al 2012), which is present in mitochondria, where it participates in transcription and replication (Zhang et al 2001). 5 0 -AMPSSBs, in which AMP is covalently linked to a 5 0 -phosphate through a pyrophosphate bond, arise from abortive DNA-ligase activity at existing SSBs and are processed by aprataxin (Ahel et al 2006), another mitochondrial protein (Sykora et al 2011).…”

Section: Single-strand Break Repair (Ssbr)mentioning

confidence: 99%

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Alexeyev

Shokolenko

Wilson

et al. 2013

Cold Spring Harbor Perspectives in Biology

375

342

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DNA molecules in mitochondria, just like those in the nucleus of eukaryotic cells, are constantly damaged by noxious agents. Eukaryotic cells have developed efficient mechanisms to deal with this assault. The process of DNA repair in mitochondria, initially believed nonexistent, has now evolved into a mature area of research. In recent years, it has become increasingly appreciated that mitochondria possess many of the same DNA repair pathways that the nucleus does. Moreover, a unique pathway that is enabled by high redundancy of the mitochondrial DNA and allows for the disposal of damaged DNA molecules operates in this organelle. In this review, we attempt to present a unified view of our current understanding of the process of DNA repair in mitochondria with an emphasis on issues that appear controversial.

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SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair

Cited by 79 publications

References 55 publications

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

TDP1 promotes assembly of non-homologous end joining protein complexes on DNA

Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2)

The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

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