Disease relevance of TDP1

• We found that deletion of the TDP1 gene in yeast confers hypersensitivity to Top2 targeting agents [1].
• Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) is a neurodegenerative disease that results from mutation of tyrosyl phosphodiesterase 1 (TDP1) [2].
• Recent studies now reveal that an ataxia gene, tyrosyl phosphodiesterase 1 (TDP1), repairs single-stranded DNA breaks in nondividing cells [3].
• The importance of Tdp1 in DNA repair is also demonstrated by the observation that a recessive mutation in the human TDP1 gene is responsible for the hereditary disorder Spinocerebellar Ataxia with Axonal Neuropathy (SCAN) [4].
• We show that the HIRAN domain is found as a standalone protein in several bacteria and prophages, or fused to other catalytic domains, such as a nuclease of the restriction endonuclease fold and TDP1-like DNA phosphoesterases, in the eukaryotes [5].

Psychiatry related information on TDP1

• Total duration of amenorrhea, body mass index, frequency of vomiting, and cigarette and alcohol consumption accounted for 40% of the variance in spinal bone mineral density measurement at Scan 1 [6].
• We studied 1,077 participants within the population-based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia [7].
• In cirrhotic patients, the prevalence of altered psychometric tests was 21% (CI95% = 14%-31%) by NCT, 23% (CI95% =15%-33%) by Scan test, and 20% (CI95% =16%-30%) by Choice2 test [8].
• To determine how relatively low-cost, risk-free, but error-prone visual field examination (VF) and high-cost, risk-prone, but accurate CT Scan (CT) and cerebral angiography (Angio) can be cost-effectively utilized to solve this diagnostic problem, the authors have developed a decision making model for the analysis of three management strategies [9].
• The CPT, measuring reaction time (Rt) and errors (er), were Font, Choice1, Choice2 and Scan test [10].

High impact information on TDP1

• Tyrosyl-DNA phosphodiesterase (Tdp1) catalyzes the hydrolysis of the tyrosyl-3' phosphate linkage found in topoisomerase I-DNA covalent complexes [11].
• The inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1), is caused by a H493R mutation in Tdp1 [11].
• SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity [11].
• Thus, the attempted repair of topoisomerase I-DNA complexes by Tdp1 unexpectedly generates a new protein-DNA complex with an apparent half-life of approximately 13 min that, in addition to the unrepaired topoisomerase I-DNA complex, may interfere with transcription and replication in human cells and contribute to the SCAN1 phenotype [11].
• The analysis of Tdp1 mutant cell lines derived from SCAN1 patients reveals that they are hypersensitive to the topoisomerase I-specific anticancer drug camptothecin (CPT), implicating Tdp1 in the repair of CPT-induced topoisomerase I damage in human cells [11].

Chemical compound and disease context of TDP1

• OBJECTIVE: The objective was to determine the role of arcitumomab (CEA-Scan; Immunomedics, Morris Plains, NJ), an anticarcinoembryonic antigen (CEA) Fab' labeled with technetium-99m, in the presurgical evaluation of patients with recurrent or metastatic colorectal carcinoma [12].
• METHODS: Ten patients with melanoma and metastases to the locoregional draining lymph nodes, clinical stage III-based on physical examination, chest radiography, lactate dehydrogenase, and histopathologic confirmation-underwent a whole-body (18)F-FLT PET scan 1 h after injection of a median 400-MBq dose (range, 185-430 MBq) of (18)F-FLT [13].
• Fast Scan was validated using a cell-based model of chronic myeloid leukemia treated with Gleevec, a specific inhibitor of aberrant Bcr-Abl protein kinase [14].
• METHODS: Serial dynamic X-ray and 2 Dimensional CAT Scan (2D-CT) studies, obtained 3, 6, and up to 12 months postoperatively, in 42 patients documented the presence of fusion or complications including plate or graft extrusion or pseudarthrosis [15].
• METHODS AND RESULTS: Twenty-four patients who presented with their first myocardial infarction and were successfully revascularized underwent cine and ceMRI of their heart within 7 days (scan 1) of the peak MB band of creatine kinase [16].

Biological context of TDP1

• Our data also suggest a role of TDP1 in the repair of DNA damage mediated by topoisomerase II, which is less clear [17].
• Since overexpression of TDP1 did not compromise cell proliferation, it could be a pleiotropic resistance mechanism in cancer therapy [17].
• When expressed in human cells as biofluorescent chimera, TDP1 appeared more mobile than topoisomerase I, less accumulated in nucleoli, and not chromosome-bound at early mitosis [17].
• Tyrosyl-DNA phosphodiesterase (TDP1) is a DNA repair enzyme that removes peptide fragments linked through tyrosine to the 3' end of DNA, and can also remove 3'-phosphoglycolates (PGs) formed by free radical-mediated DNA cleavage [18].
• In addition, this role is redundant in lower eukaryotes, and Tdp1 mutations alone confer little phenotype [2].

Anatomical context of TDP1

• Inhibition of human tyrosyl-DNA phosphodiesterase by aminoglycoside antibiotics and ribosome inhibitors [19].
• In eukaryotic cells, this type of linkage is found in stalled topoisomerase I-DNA covalent complexes, and Tdp1 has been implicated in the repair of such complexes in vivo [20].
• A newly discovered human analogue of a bed bug apyrase, which we named hSCAN-1 for human soluble calcium-activated nucleotidase-1, was expressed in bacteria, refolded from inclusion bodies, purified, and characterized [21].
• The averaged thickness of nonenhanced myocardium in the infarct segments significantly increased from scan 1 to 2 (5.2 +/- 3.0 mm vs. 6.6 +/- 3.2 mm, p < 0.001) [22].
• Forty-three of the 44 had cystic duct obstruction demonstrated on H.I.D.A. Scan (one false negative) [23].

Associations of TDP1 with chemical compounds

• Tyrosyl DNA phosphodiesterase 1 (TDP1) is a repair enzyme that removes adducts, e.g. of topoisomerase I from the 3'-phosphate of DNA breaks [17].
• Inhibition by neomycin can be overcome with excess Tdp1 and is greatest at low pH [19].
• To our knowledge, aminoglycoside antibiotics and the ribosome inhibitors thiostrepton, clindamycin-2-phosphate, and puromycin are the first reported pharmacological Tdp1 inhibitors [19].
• In the present study, we report that neomycin inhibits Tdp1 more effectively than the related aminoglycosides paromomycin and lividomycin A [19].
• Inhibition of Tdp1 by neomycin is observed both with single- and double-stranded substrates but is slightly stronger with duplex DNA, which is different from aclarubicin, which only inhibits Tdp1 with the double-stranded substrate [19].

Regulatory relationships of TDP1

• Inhibiting Tdp1 has the potential to enhance the anticancer activity of Top1 inhibitors (http://discover.nci.nih.gov/pommier/pommier.htm) and to act as antiproliferative agents [19].

Other interactions of TDP1

• Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA [1].
• Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions [24].
• The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily [25].

Analytical, diagnostic and therapeutic context of TDP1

• Site-directed mutagenesis of human soluble calcium-activated nucleotidase 1 (hSCAN-1): identification of residues essential for enzyme activity and the Ca(2+)-induced conformational change [26].
• By multiple sequence alignment, eight regions that are highly conserved in the hSCAN-1 family were identified and named [26].
• No significant changes in bone mineral density were observed at Scan 2 despite increases in body mass index [6].
• Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation [27].
• DESIGN: The Rotterdam Scan Study, a prospective population-based cohort study [28].

References