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Gene Review

TDP1  -  tyrosyl-DNA phosphodiesterase 1

Homo sapiens

Synonyms: FLJ11090, SCAN1, Tyr-DNA phosphodiesterase 1, Tyrosyl-DNA phosphodiesterase 1
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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


Regulatory relationships of TDP1

  • Inhibiting Tdp1 has the potential to enhance the anticancer activity of Top1 inhibitors ( and to act as antiproliferative agents [19].

Other interactions of TDP1


Analytical, diagnostic and therapeutic context of TDP1


  1. Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage. Nitiss, K.C., Malik, M., He, X., White, S.W., Nitiss, J.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  2. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. El-Khamisy, S.F., Saifi, G.M., Weinfeld, M., Johansson, F., Helleday, T., Lupski, J.R., Caldecott, K.W. Nature (2005) [Pubmed]
  3. Breaks in coordination: DNA repair in inherited ataxia. Paulson, H.L., Miller, V.M. Neuron (2005) [Pubmed]
  4. Tyrosyl-DNA phosphodiesterase (Tdp1) (3'-phosphotyrosyl DNA phosphodiesterase). Raymond, A.C., Burgin, A.B. Meth. Enzymol. (2006) [Pubmed]
  5. The HIRAN domain and recruitment of chromatin remodeling and repair activities to damaged DNA. Iyer, L.M., Babu, M.M., Aravind, L. Cell Cycle (2006) [Pubmed]
  6. Factors predictive of bone mineral density in eating-disordered women: a longitudinal study. Baker, D., Roberts, R., Towell, T. The International journal of eating disorders. (2000) [Pubmed]
  7. Plasma amyloid beta, apolipoprotein E, lacunar infarcts, and white matter lesions. van Dijk, E.J., Prins, N.D., Vermeer, S.E., Hofman, A., van Duijn, C.M., Koudstaal, P.J., Breteler, M.M. Ann. Neurol. (2004) [Pubmed]
  8. Clinical features and survivial of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Amodio, P., Del Piccolo, F., Marchetti, P., Angeli, P., Iemmolo, R., Caregaro, L., Merkel, C., Gerunda, G., Gatta, A. Hepatology (1999) [Pubmed]
  9. Diagnostic strategies in the management of unexplained visual loss. A cost-benefit analysis. Acosta, P.C., Trobe, J.D., Shuster, J.J., Krischer, J.P. Medical decision making : an international journal of the Society for Medical Decision Making. (1981) [Pubmed]
  10. Diagnostic tools for the detection of subclinical hepatic encephalopathy: comparison of standard and computerized psychometric tests with spectral-EEG. Amodio, P., Quero, J.C., Del Piccolo, F., Gatta, A., Schalm, S.W. Metabolic brain disease. (1996) [Pubmed]
  11. SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity. Interthal, H., Chen, H.J., Kehl-Fie, T.E., Zotzmann, J., Leppard, J.B., Champoux, J.J. EMBO J. (2005) [Pubmed]
  12. Use of carcinoembryonic antigen radioimmunodetection and computed tomography for predicting the resectability of recurrent colorectal cancer. Hughes, K., Pinsky, C.M., Petrelli, N.J., Moffat, F.L., Patt, Y.Z., Hammershaimb, L., Goldenberg, D.M. Ann. Surg. (1997) [Pubmed]
  13. 3'-18F-fluoro-3'-deoxy-L-thymidine: a new tracer for staging metastatic melanoma? Cobben, D.C., Jager, P.L., Elsinga, P.H., Maas, B., Suurmeijer, A.J., Hoekstra, H.J. J. Nucl. Med. (2003) [Pubmed]
  14. Use of moving optical gradient fields for analysis of apoptotic cellular responses in a chronic myeloid leukemia cell model. Forster, A.H., Wang, M.M., Butler, W.F., Chachisvilis, M., Chung, T.D., Esener, S.C., Hall, J.M., Kibar, O., Lykstad, K., Marchand, P.J., Mercer, E.M., Pestana, L.M., Sur, S., Tu, E., Yang, R., Zhang, H., Kariv, I. Anal. Biochem. (2004) [Pubmed]
  15. Anterior cervical dynamic ABC plating with single level corpectomy and fusion in forty-two patients. Epstein, N.E. Spinal Cord (2003) [Pubmed]
  16. Transmural extent of acute myocardial infarction predicts long-term improvement in contractile function. Choi, K.M., Kim, R.J., Gubernikoff, G., Vargas, J.D., Parker, M., Judd, R.M. Circulation (2001) [Pubmed]
  17. TDP1 overexpression in human cells counteracts DNA damage mediated by topoisomerases I and II. Barthelmes, H.U., Habermeyer, M., Christensen, M.O., Mielke, C., Interthal, H., Pouliot, J.J., Boege, F., Marko, D. J. Biol. Chem. (2004) [Pubmed]
  18. Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Zhou, T., Lee, J.W., Tatavarthi, H., Lupski, J.R., Valerie, K., Povirk, L.F. Nucleic Acids Res. (2005) [Pubmed]
  19. Inhibition of human tyrosyl-DNA phosphodiesterase by aminoglycoside antibiotics and ribosome inhibitors. Liao, Z., Thibaut, L., Jobson, A., Pommier, Y. Mol. Pharmacol. (2006) [Pubmed]
  20. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. Interthal, H., Chen, H.J., Champoux, J.J. J. Biol. Chem. (2005) [Pubmed]
  21. Bacterial expression and characterization of a novel, soluble, calcium-binding, and calcium-activated human nucleotidase. Murphy, D.M., Ivanenkov, V.V., Kirley, T.L. Biochemistry (2003) [Pubmed]
  22. Late gadolinium-enhanced magnetic resonance imaging in acute and chronic myocardial infarction. Improved prediction of regional myocardial contraction in the chronic state by measuring thickness of nonenhanced myocardium. Ichikawa, Y., Sakuma, H., Suzawa, N., Kitagawa, K., Makino, K., Hirano, T., Takeda, K. J. Am. Coll. Cardiol. (2005) [Pubmed]
  23. The role of H.I.D.A./P.I.P.I.D.A. scanning in diagnosing cystic duct obstruction. Suarez, C.A., Block, F., Bernstein, D., Serafini, A., Rodman, G., Zeppa, R. Ann. Surg. (1980) [Pubmed]
  24. Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. Plo, I., Liao, Z.Y., Barceló, J.M., Kohlhagen, G., Caldecott, K.W., Weinfeld, M., Pommier, Y. DNA Repair (Amst.) (2003) [Pubmed]
  25. The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Interthal, H., Pouliot, J.J., Champoux, J.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  26. 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. Yang, M., Kirley, T.L. Biochemistry (2004) [Pubmed]
  27. PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity. Soncini, C., Carpinelli, P., Gianellini, L., Fancelli, D., Vianello, P., Rusconi, L., Storici, P., Zugnoni, P., Pesenti, E., Croci, V., Ceruti, R., Giorgini, M.L., Cappella, P., Ballinari, D., Sola, F., Varasi, M., Bravo, R., Moll, J. Clin. Cancer Res. (2006) [Pubmed]
  28. Cerebral white matter lesions and the risk of dementia. Prins, N.D., van Dijk, E.J., den Heijer, T., Vermeer, S.E., Koudstaal, P.J., Oudkerk, M., Hofman, A., Breteler, M.M. Arch. Neurol. (2004) [Pubmed]
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