subject:(TDP1)

University of Edinburgh

1. Carloni, Roberta. Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei.

Degree: PhD, 2014, University of Edinburgh

URL: http://hdl.handle.net/1842/18015

► In order to evaluate the suitability of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) as a potential drug target for an anti-parasite therapy, we… (more)

Subjects/Keywords: 572.8; DNA repair; topoisomerase; TDP1; tyrosyl-DNA phosphodiesterase 1; T. brucei

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Carloni, R. (2014). Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei. (Doctoral Dissertation). University of Edinburgh. Retrieved from http://hdl.handle.net/1842/18015

Chicago Manual of Style (16^th Edition):

Carloni, Roberta. “Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei.” 2014. Doctoral Dissertation, University of Edinburgh. Accessed March 05, 2021. http://hdl.handle.net/1842/18015.

MLA Handbook (7^th Edition):

Carloni, Roberta. “Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei.” 2014. Web. 05 Mar 2021.

Vancouver:

Carloni R. Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei. [Internet] [Doctoral dissertation]. University of Edinburgh; 2014. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/1842/18015.

Council of Science Editors:

Carloni R. Functional analysis of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) in Trypanosoma brucei brucei. [Doctoral Dissertation]. University of Edinburgh; 2014. Available from: http://hdl.handle.net/1842/18015

2. Cristini, Agnese. DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription.

Degree: Docteur es, Biotechnologies, cancérologie, 2015, Université Toulouse III – Paul Sabatier

URL: http://www.theses.fr/2015TOU30276

►

La topoisomérase I (Top1) élimine les surenroulements de l'ADN générés lors de la transcription en produisant transitoirement des complexes de clivage Top1-ADN (Top1cc). Ces Top1cc… (more)

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La topoisomérase I (Top1) élimine les surenroulements de l'ADN générés lors de la transcription en produisant transitoirement des complexes de clivage Top1-ADN (Top1cc). Ces Top1cc transitoires peuvent être stabilisés par les camptothécines, dont sont dérivés des agents anticancéreux, et par les fréquentes altérations de l'ADN. Bien que les Top1cc stabilisés soient des lésions qui bloquent efficacement la transcription, la compréhension des processus moléculaires qui résultent du blocage des complexes transcriptionnels par les Top1cc est encore limitée. Des travaux précédents ont montré que les Top1cc stabilisés produisent des cassures double-brin (DSBs) de l'ADN dépendantes de la transcription qui activent ATM. Dans ce projet, nous avons utilisé des cellules quiescentes traitées avec la camptothécine pour induire des Top1cc bloquant la transcription et nous avons étudié les mécanismes de la production et de la signalisation des DSBs. Nous montrons que les DSBs sont produites préférentiellement dans les régions sub-télomériques lors de la réparation des Top1cc bloquant la transcription par les cassures simple-brin de l'ADN générées après la protéolyse de la Top1 et avant l'action de Tdp1. L'analyse de la signalisation de ces DSBs révèle une nouvelle fonction de DNA-PK dans la promotion de l'ubiquitinylation conduisant (i) à l'activité complète d'ATM aux sites des DSBs en favorisant l'ubiquitination d'H2AX et H2A, et (ii) à l'augmentation de la réparation des Top1cc en favorisant la protéolyse de la Top1. Enfin, nous montrons que les DSBs co-transcriptionnelles induisent la mort des cellules quiescentes. L'ensemble de ces résultats apportent un nouvel aperçu des réponses cellulaires aux camptothécines, et suggèrent que les DSBs qui résultent des Top1cc bloquant la transcription puissent contribuer à la pathogénèse du syndrome neurodégénératif SCAN1, qui est causé par une déficience en Tdp1.

Topoisomerase I (Top1) removes DNA supercoiling generated during transcription by producing Top1-DNA cleavage complexes (Top1cc). These transient Top1cc can be stabilized by camptothecins, from which anticancer drugs are derived, and by common DNA alterations. Although stabilized Top1cc are potent transcription-blocking lesions, our understanding regarding the molecular processes resulting from the stalling of transcription complexes by Top1cc is currently limited. Previous work showed that stabilized Top1cc produce transcription-dependent DNA double-strand breaks (DSBs) that activate ATM signalling. In this project, we used camptothecin-treated quiescent cells to induce transcription-blocking Top1cc and study the mechanisms of DSB production and signalling. We show that DSBs form preferentially at subtelomeric regions during the repair of transcription-blocking Top1cc from DNA single-strand breaks generated after Top1 proteolysis and before Tdp1 action. Analysis of DSB signalling reveals a novel function of DNA-PK in promoting protein ubiquitination leading (i) to full ATM activity at DSB sites by promoting H2AX and H2A…

Advisors/Committee Members: Sordet, Olivier (thesis director).

Subjects/Keywords: Topoisomérase; Cassures double-brin; DNA-PK; Ubiquitine; Camptothécine; Transcription; Tdp1; Dommage à l'ADN; Topoisomerase; Double-strand breaks; DNA-PK; Ubiquitin; Camptothecin; Transcription; Tdp1; DNA damage

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Cristini, A. (2015). DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription. (Doctoral Dissertation). Université Toulouse III – Paul Sabatier. Retrieved from http://www.theses.fr/2015TOU30276

Chicago Manual of Style (16^th Edition):

Cristini, Agnese. “DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription.” 2015. Doctoral Dissertation, Université Toulouse III – Paul Sabatier. Accessed March 05, 2021. http://www.theses.fr/2015TOU30276.

MLA Handbook (7^th Edition):

Cristini, Agnese. “DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription.” 2015. Web. 05 Mar 2021.

Vancouver:

Cristini A. DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription. [Internet] [Doctoral dissertation]. Université Toulouse III – Paul Sabatier; 2015. [cited 2021 Mar 05]. Available from: http://www.theses.fr/2015TOU30276.

Council of Science Editors:

Cristini A. DNA double-strand break formation and signalling in response to transcription-blocking topoisomerase I complexes : Formation et signalisation des cassures double-brin de l'ADN lors d'un blocage de la transcription. [Doctoral Dissertation]. Université Toulouse III – Paul Sabatier; 2015. Available from: http://www.theses.fr/2015TOU30276

Virginia Commonwealth University

3. Zhou, Tong. ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS.

Degree: MS, Pharmacology & Toxicology, 2012, Virginia Commonwealth University

URL: https://doi.org/10.25772/6KMG-K239 ; https://scholarscompass.vcu.edu/etd/2933

► DNA DSBs are most toxic to cells because they can lead to genomic rearrangements and even cell death. Most DSBs induced by ionizing radiation or… (more)

▼ DNA DSBs are most toxic to cells because they can lead to genomic rearrangements and even cell death. Most DSBs induced by ionizing radiation or radiomimetic drugs such as calicheamicin and bleomycin, bear 3′-phosphate or 3′- PG moieties that must be removed to allow subsequent gap filling and ligation. DSBs can be repaired by two main pathways: the homologous recombination (HR) pathway and the non-homologous end-joining (NHEJ) pathway, NHEJ is the primary repair pathway in mammalian cells. While HR repairs single strand breaks (SSBs) or DSBs accurately by using an undamaged copy of the sequence mostly at late S phase and G2 phase, the NHEJ pathway repairs DSBs without the requirement for sequence homology in a processing that may be error-free or error- prone and is most active at G1 phase. TDP1 is a DNA repair enzyme in both pathways, It associates with DNA SSB repair proteins XRCC1 and DNA ligase III and plays a role in processing of topoisomerase I- mediated SSBs. Our early results suggested that TDP1 also can remove protruding 3’- PG and other 3’ blocks from DSBs ends in vitro. A homozygous H493R mutation in the active site of TDP1 causes spinocerebellar ataxia with axonal neuropathy (SCAN1), a rare autosomal recessive genetic disease with neurological symptoms including peripheral neuropathy. DNA damage and misrepair can be determined by measuring the incidence of chromosomal aberrations such as rings, breaks, dicentrics, acentric fragments, and translocations in metaphase cells, and micronuclei in interphase cells. To assess the possible role of TDP1 in DSB repair in intact cells, the radiosensitivity of SCAN1 cells was determined by using a dose-fractionation method of irradiation. The data indicated that, when exposed to fractionated radiation doses, the SCAN1 cells were more sensitive than normal cells. Moreover, following treatment of cells with calicheamicin, SCAN1 cells showed a significantly higher incidence of dicentric chromosomes, acentric fragments, and micronuclei compared to normal cells, indicating that calicheamicin-induced DSBs were repaired less accurately and less efficiently, or more slowly in SCAN1 cells than in normal cells. All these results are consistent with a role for TDP1 in repair of 3’-PG DSBs in vivo. Oxidative stress is thought to induce replicative senescence and DNA damage in mouse embryo fibroblasts (MEFs). To determine the possible roles of oxidative stress on Tdp1-deficient MEFs, Tdp1-knockout MEFs and normal MEFs were cultured in 20% oxygen (atmospheric) and 3% (physiological) oxygen. The data from growth assays indicated that normal MEFs showed replicative senescence in 20% oxygen but not in 3% oxygen. Tdp1-knockout MEFs showed very poor growth compared to Tdp1 normal MEFs in both oxygen conditions, clearly suggesting an influence of repair of Tdp1 on oxidative stress induced DNA-DSBs in MEFs. Taken together, our results indicated that TDP1 is capable of removing protruding 3’-PG from DSB ends in intact cells. Moreover, DSBs induced by oxidative stress were repaired more… Advisors/Committee Members: Lawrence Povirk.

Subjects/Keywords: TDP1; SCAN1; NHEJ; DSB; IR; MEFs.; Medical Pharmacology; Medical Sciences; Medicine and Health Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zhou, T. (2012). ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS. (Thesis). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/6KMG-K239 ; https://scholarscompass.vcu.edu/etd/2933

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Zhou, Tong. “ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS.” 2012. Thesis, Virginia Commonwealth University. Accessed March 05, 2021. https://doi.org/10.25772/6KMG-K239 ; https://scholarscompass.vcu.edu/etd/2933.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Zhou, Tong. “ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS.” 2012. Web. 05 Mar 2021.

Vancouver:

Zhou T. ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS. [Internet] [Thesis]. Virginia Commonwealth University; 2012. [cited 2021 Mar 05]. Available from: https://doi.org/10.25772/6KMG-K239 ; https://scholarscompass.vcu.edu/etd/2933.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Zhou T. ROLE OF TYROSYL-DNA PHOSPHODIESTERASE (TDP 1) ON REPAIR OF 3′-PHOSPHOGLYCOLATE (3′- PG) TERMINATED DNA DOUBLE-STRAND BREAKS (DSBS) AND IN RESPONSE TO OXIDATIVE STRESS. [Thesis]. Virginia Commonwealth University; 2012. Available from: https://doi.org/10.25772/6KMG-K239 ; https://scholarscompass.vcu.edu/etd/2933

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Illinois – Chicago

4. Li, Jing. Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ).

Degree: 2017, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/22078

► The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. Major DSB repair pathways in mammalian cells include homologous recombination… (more)

▼ The repair of DNA double-strand breaks (DSB) is central to the maintenance of genomic integrity. Major DSB repair pathways in mammalian cells 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 suggest that NHEJ includes mechanisms to minimize error. In yeast, mutations of tyrosyl-DNA phosphodiesterase 1 (TDP1) reduced NHEJ fidelity. We are investigating the role of TDP1 in NHEJ in human cells. Using affinity capture chromatography, we found human TDP1 physically interacted with the required NHEJ protein -XLF. This interaction also stimulated DNA binding for both TDP1 and XLF, and formation of TDP1:XLF:DNA complexes. TDP1 can remove adducts from DNA 3’ ends, and TDP1:XLF interactions stimulated this activity on double-stranded, but not on single-stranded DNA. To investigate role of TDP1 in NHEJ in human cells, we used CRISPR/Cas9-mediated genome editing to generate TDP1-knockout HEK 293 cells, which showed an expected increase sensitivity to Topoisomerase 1 poisoning and ionizing radiation. Using a chromosomally- integrated end-joining reporter substrate, we observed an average 4-fold reduction in repair of I-SceI-induced DSBs in TDP1-KO cells as compared to wild type cells. These data indicate that, in human cells, TDP1 contributes to repair of DSBs that lack 3’ end damage. NextGen sequencing of end-joining junctions generated in this reporter system showed that TDP1 deficiency resulted in increased use of microhomology in joining. Within the N-terminal domain of TDP1, phosphorylation at serine 81 (S81) has been reported to regulate interaction with DNA repair factors, including DNA ligase III, XRCC4 and PARP1. We observed that the TDP1-S81 phosphomimetic, TDP1-S81E, had 10-fold reduced XLF binding, and ectopic expression of TDP1-S81E in TDP1-knockout cells failed to restore NHEJ activity. These data suggest that phosphorylation of TDP1-S81 regulates TDP1 participation in NHEJ, and may also direct TDP1 towards DNA ligase III-related pathways. Our observations support the hypothesis that TDP1 participates in mammalian NHEJ, and contribute important details to our understanding of DNA repair. Advisors/Committee Members: Hanakahi, Les (advisor), Nitiss, John (committee member), Mankin, Alexander (committee member), Burdette, Joanna (committee member), Thomas, Douglas (committee member), Hanakahi, Les (chair).

Subjects/Keywords: tyrosyl-DNA phosphodiesterase 1 (TDP1); non-homologous end joining (NHEJ); DNA double-strand breaks (DSB)

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Li, J. (2017). Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ). (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/22078

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Li, Jing. “Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ).” 2017. Thesis, University of Illinois – Chicago. Accessed March 05, 2021. http://hdl.handle.net/10027/22078.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Li, Jing. “Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ).” 2017. Web. 05 Mar 2021.

Vancouver:

Li J. Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ). [Internet] [Thesis]. University of Illinois – Chicago; 2017. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/10027/22078.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Li J. Investigating Role of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) In Non-Homologous End Joining (NHEJ). [Thesis]. University of Illinois – Chicago; 2017. Available from: http://hdl.handle.net/10027/22078

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Kyoto University

5. Takiuchi, Yoko. HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia .

Degree: 2018, Kyoto University

URL: http://hdl.handle.net/2433/232095

Subjects/Keywords: ATL; ABC; TDP1; NRF-1; HBZ

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Takiuchi, Y. (2018). HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia . (Thesis). Kyoto University. Retrieved from http://hdl.handle.net/2433/232095

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Takiuchi, Yoko. “HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia .” 2018. Thesis, Kyoto University. Accessed March 05, 2021. http://hdl.handle.net/2433/232095.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Takiuchi, Yoko. “HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia .” 2018. Web. 05 Mar 2021.

Vancouver:

Takiuchi Y. HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia . [Internet] [Thesis]. Kyoto University; 2018. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/2433/232095.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Takiuchi Y. HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia . [Thesis]. Kyoto University; 2018. Available from: http://hdl.handle.net/2433/232095

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

6. Tada, Kohei. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする.

Degree: 博士(医学), 2015, Kyoto University / 京都大学

URL: http://hdl.handle.net/2433/202797 ; http://dx.doi.org/10.14989/doctor.k19363

新制・課程博士

甲第19363号

医博第4040号

Subjects/Keywords: Adult T cell leukemia; Abacavir; TDP1; NRTI; chemotherapy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tada, K. (2015). Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする. (Thesis). Kyoto University / 京都大学. Retrieved from http://hdl.handle.net/2433/202797 ; http://dx.doi.org/10.14989/doctor.k19363

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tada, Kohei. “Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする.” 2015. Thesis, Kyoto University / 京都大学. Accessed March 05, 2021. http://hdl.handle.net/2433/202797 ; http://dx.doi.org/10.14989/doctor.k19363.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tada, Kohei. “Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする.” 2015. Web. 05 Mar 2021.

Vancouver:

Tada K. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする. [Internet] [Thesis]. Kyoto University / 京都大学; 2015. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/2433/202797 ; http://dx.doi.org/10.14989/doctor.k19363.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tada K. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia : 抗HIV薬アバカビルは、TDP1が欠損している成人T細胞白血病を標的とする. [Thesis]. Kyoto University / 京都大学; 2015. Available from: http://hdl.handle.net/2433/202797 ; http://dx.doi.org/10.14989/doctor.k19363

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Tada, Kohei. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia .

Degree: 2015, Kyoto University

URL: http://hdl.handle.net/2433/202797

Subjects/Keywords: Adult T cell leukemia; Abacavir; TDP1; NRTI; chemotherapy

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tada, K. (2015). Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia . (Thesis). Kyoto University. Retrieved from http://hdl.handle.net/2433/202797

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tada, Kohei. “Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia .” 2015. Thesis, Kyoto University. Accessed March 05, 2021. http://hdl.handle.net/2433/202797.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tada, Kohei. “Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia .” 2015. Web. 05 Mar 2021.

Vancouver:

Tada K. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia . [Internet] [Thesis]. Kyoto University; 2015. [cited 2021 Mar 05]. Available from: http://hdl.handle.net/2433/202797.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tada K. Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia . [Thesis]. Kyoto University; 2015. Available from: http://hdl.handle.net/2433/202797

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

8. Kawale, Ajinkya S. PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE.

Degree: PhD, Pharmacology & Toxicology, 2018, Virginia Commonwealth University

URL: https://doi.org/10.25772/HX1V-JT51 ; https://scholarscompass.vcu.edu/etd/5329

► DNA double-strand breaks (DSBs) containing unligatable termini are potent cytotoxic lesions leading to growth arrest or cell death. The Artemis nuclease and tyrosyl-DNA phosphodiesterase… (more)

▼ DNA double-strand breaks (DSBs) containing unligatable termini are potent cytotoxic lesions leading to growth arrest or cell death. The Artemis nuclease and tyrosyl-DNA phosphodiesterase (TDP1) are each capable of resolving protruding 3′-phosphoglycolate (PG) termini of DNA double-strand breaks (DSBs). Consequently, a knockout of Artemis and a knockout/knockdown of TDP1 rendered cells sensitive to the radiomimetic agent neocarzinostatin (NCS), which induces 3′-PG-terminated DSBs. Unexpectedly, however, a knockdown or knockout of TDP1 in Artemis-null cells did not confer any greater sensitivity than either deficiency alone, indicating a strict epistasis between TDP1 and Artemis. Moreover, a deficiency in Artemis, but not TDP1, resulted in a fraction of unrepaired DSBs, which were assessed as 53BP1 foci. Conversely, a deficiency in TDP1, but not Artemis, resulted in a dramatic increase in dicentric chromosomes following NCS treatment. An inhibitor of DNA-dependent protein kinase, a key regulator of the classical nonhomologous end joining (C-NHEJ) pathway sensitized cells to NCS but eliminated the sensitizing effects of both TDP1 and Artemis deficiencies. Moreover, Polynucleotide Kinase/ Phosphatase (PNKP) is known to process 3′-phosphates and 5′-hydroxyls during DSB repair. PNKP-deficiency sensitized both HCT116 and HeLa cells to 3′-phosphate ended DSBs formed upon radiation and radiomimetic drug treatment. The increased cytotoxicity in the absence of PNKP was synonymous with persistent, un-rejoined 3′-phosphate-ended DSBs. However, DNA-PK deficiency sensitized PNKP^-/- cells to low doses of NCS suggesting that, in the absence of PNKP, alternative enzyme(s) can remove 3′-phosphates in a DNA-PK-dependent manner. These results suggest that TDP1 and Artemis perform different functions in the repair of terminally blocked DSBs by the C-NHEJ pathway, and that whereas an Artemis deficiency prevents end joining of some DSBs, a TDP1 deficiency tends to promote DSB mis-joining. In addition, loss of PNKP significantly sensitizes cells to 3′-phosphate-ended DSBs due to a defect in 3′-dephosphorylation. Advisors/Committee Members: Dr. Lawrence F. Povirk.

Subjects/Keywords: TDP1; Artemis; Epistasis; Double-strand break repair; NHEJ; Biochemistry; Molecular Biology; Molecular Genetics

…51 3.4 TDP1 activity assay… …59 4.1 Generation of TDP1-mutant (shTDP1 and TDP1-/-) cell lines… …59 4.2 TDP1 deficient cells are hypersensitive to ionizing radiation and radiomimetic… …agents. ... 63 4.3 Generation of TDP1 and Artemis double knockouts… …66 4.4 TDP1 and Artemis are epistatic for the repair of 3′-PG DSBs via NHEJ…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kawale, A. S. (2018). PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/HX1V-JT51 ; https://scholarscompass.vcu.edu/etd/5329

Chicago Manual of Style (16^th Edition):

Kawale, Ajinkya S. “PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE.” 2018. Doctoral Dissertation, Virginia Commonwealth University. Accessed March 05, 2021. https://doi.org/10.25772/HX1V-JT51 ; https://scholarscompass.vcu.edu/etd/5329.

MLA Handbook (7^th Edition):

Kawale, Ajinkya S. “PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE.” 2018. Web. 05 Mar 2021.

Vancouver:

Kawale AS. PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2018. [cited 2021 Mar 05]. Available from: https://doi.org/10.25772/HX1V-JT51 ; https://scholarscompass.vcu.edu/etd/5329.

Council of Science Editors:

Kawale AS. PROCESSING OF 3′-BLOCKED DNA DOUBLE-STRAND BREAKS BY TYROSYL-DNA PHOSPHODIESTERASE 1, ARTEMIS AND POLYNUCLEOTIDE KINASE/ PHOSPHATASE. [Doctoral Dissertation]. Virginia Commonwealth University; 2018. Available from: https://doi.org/10.25772/HX1V-JT51 ; https://scholarscompass.vcu.edu/etd/5329

Virginia Commonwealth University

9. Hawkins, Amy. Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling.

Degree: PhD, Human Genetics, 2009, Virginia Commonwealth University

URL: https://doi.org/10.25772/MZAH-T285 ; https://scholarscompass.vcu.edu/etd/34

► This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in… (more)

▼ This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in a mouse model of hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), a congenital neurodegenerative disease. SCAN1 is caused by a homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1). To address how the H493R mutation elicits the specific pathologies of SCAN1 and to further elucidate the role of TDP1 in processing DNA end modifications, we generated a Tdp1 knockout mouse and characterized their behavior and specific repair deficiencies in extracts of embryonic fibroblasts from these animals. While Tdp1(-/-) mice appear phenotypically normal, extracts from Tdp1(-/-) fibroblasts exhibited deficiencies in processing 3'-phosphotyrosyl single-strand breaks and 3'-phosphoglycolate (PG) double-strand breaks (DSBs). Supplementing Tdp1(-/-) extracts with H493R TDP1 partially restored processing of 3'-phosphotyrosyl single-strand breaks, but with evidence of persistent covalent adducts between TDP1 and DNA, consistent with a proposed intermediate-stabilization effect of the SCAN1 mutation. However, H493R TDP1 supplementation had no effect on PG termini on 3' overhangs of DSBs; these remained completely unprocessed. Altogether, these results suggest that for 3'-PG overhang lesions, the SCAN1 mutation confers loss of function, while for 3'-phosphotyrosyl lesions, the mutation uniquely stabilizes a reaction intermediate. Furthermore, there is evidence that TDP1 also localizes to mitochondria, and mitochondrial DNA damage should not be excluded from significantly contributing to SCAN1 pathology. The effect of ATM signaling on NHEJ was investigated via a novel vector that allows for inducing I-SceI-mediated DNA DSBs that can then be analyzed for NHEJ repair events by fluorescence- and PCR-based methods. Using highly specific DNA kinase inhibitors and the repair cassette, we showed that inhibiting ATM reduced NHEJ by 80% in a U87 glioma model. Analysis of the PCR products from the NHEJ repair vector by PsiI restriction cleavage allowed for assessment of the fidelity of the NHEJ repair: inhibiting ATM reduced high-fidelity NHEJ by 40%. Together, these results suggest that ATM is critical for NHEJ of I-SceI DSBs and for high-fidelity repair, possibly due to ATM's effects on chromatin architecture surrounding the DSB. Advisors/Committee Members: Kristoffer Valerie, Lawrence Povirk.

Subjects/Keywords: DNA repair; TDP1; ATM; radiation; SCAN1; NHEJ; Medical Genetics; Medical Sciences; Medicine and Health Sciences

Record Details Similar Records Cite « Share

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Hawkins, A. (2009). Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling. (Doctoral Dissertation). Virginia Commonwealth University. Retrieved from https://doi.org/10.25772/MZAH-T285 ; https://scholarscompass.vcu.edu/etd/34

Chicago Manual of Style (16^th Edition):

Hawkins, Amy. “Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling.” 2009. Doctoral Dissertation, Virginia Commonwealth University. Accessed March 05, 2021. https://doi.org/10.25772/MZAH-T285 ; https://scholarscompass.vcu.edu/etd/34.

MLA Handbook (7^th Edition):

Hawkins, Amy. “Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling.” 2009. Web. 05 Mar 2021.

Vancouver:

Hawkins A. Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling. [Internet] [Doctoral dissertation]. Virginia Commonwealth University; 2009. [cited 2021 Mar 05]. Available from: https://doi.org/10.25772/MZAH-T285 ; https://scholarscompass.vcu.edu/etd/34.

Council of Science Editors:

Hawkins A. Nonhomologous end-joining: TDP1-mediated processing, ATM-mediated signaling. [Doctoral Dissertation]. Virginia Commonwealth University; 2009. Available from: https://doi.org/10.25772/MZAH-T285 ; https://scholarscompass.vcu.edu/etd/34

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