| Structural highlights
Disease
[TYDP1_HUMAN] Defects in TDP1 are the cause of spinocerebellar ataxia autosomal recessive with axonal neuropathy (SCAN1) [MIM:607250]. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence.[1] [2] [3] [4] [5]
Function
[TYDP1_HUMAN] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.[6] [7] [8] [9] [10]
Publication Abstract from PubMed
Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3'-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA-protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1-DNA complexes capture the DNA repair machinery after 3'-end cleavage; these reveal how Tdp1 coordinates the 3'-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the -3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3'-end processing by Tdp1.
Structural basis for DNA 3'-end processing by human tyrosyl-DNA phosphodiesterase 1.,Flett FJ, Ruksenaite E, Armstrong LA, Bharati S, Carloni R, Morris ER, Mackay CL, Interthal H, Richardson JM Nat Commun. 2018 Jan 2;9(1):24. doi: 10.1038/s41467-017-02530-z. PMID:29295983[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem. 2005 Oct 28;280(43):36518-28. Epub 2005 Aug 31. PMID:16141202 doi:M508898200
- ↑ Zhou T, Lee JW, Tatavarthi H, Lupski JR, Valerie K, Povirk LF. Deficiency in 3'-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res. 2005 Jan 12;33(1):289-97. Print 2005. PMID:15647511 doi:33/1/289
- ↑ Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, Armstrong D, Mao Y, Quiocho FA, Roa BB, Nakagawa M, Stockton DW, Lupski JR. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet. 2002 Oct;32(2):267-72. Epub 2002 Sep 16. PMID:12244316 doi:10.1038/ng987
- ↑ Hirano R, Interthal H, Huang C, Nakamura T, Deguchi K, Choi K, Bhattacharjee MB, Arimura K, Umehara F, Izumo S, Northrop JL, Salih MA, Inoue K, Armstrong DL, Champoux JJ, Takashima H, Boerkoel CF. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? EMBO J. 2007 Nov 14;26(22):4732-43. Epub 2007 Oct 18. PMID:17948061 doi:7601885
- ↑ Interthal H, Chen HJ, Kehl-Fie TE, Zotzmann J, Leppard JB, Champoux JJ. SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity. EMBO J. 2005 Jun 15;24(12):2224-33. Epub 2005 May 26. PMID:15920477 doi:7600694
- ↑ Inamdar KV, Pouliot JJ, Zhou T, Lees-Miller SP, Rasouli-Nia A, Povirk LF. Conversion of phosphoglycolate to phosphate termini on 3' overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J Biol Chem. 2002 Jul 26;277(30):27162-8. Epub 2002 May 21. PMID:12023295 doi:10.1074/jbc.M204688200
- ↑ Raymond AC, Rideout MC, Staker B, Hjerrild K, Burgin AB Jr. Analysis of human tyrosyl-DNA phosphodiesterase I catalytic residues. J Mol Biol. 2004 May 14;338(5):895-906. PMID:15111055 doi:10.1016/j.jmb.2004.03.013
- ↑ Raymond AC, Staker BL, Burgin AB Jr. Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1). J Biol Chem. 2005 Jun 10;280(23):22029-35. Epub 2005 Apr 4. PMID:15811850 doi:M502148200
- ↑ Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem. 2005 Oct 28;280(43):36518-28. Epub 2005 Aug 31. PMID:16141202 doi:M508898200
- ↑ Gao R, Huang SY, Marchand C, Pommier Y. Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. J Biol Chem. 2012 Aug 31;287(36):30842-52. doi: 10.1074/jbc.M112.393983. Epub, 2012 Jul 20. PMID:22822062 doi:10.1074/jbc.M112.393983
- ↑ Flett FJ, Ruksenaite E, Armstrong LA, Bharati S, Carloni R, Morris ER, Mackay CL, Interthal H, Richardson JM. Structural basis for DNA 3'-end processing by human tyrosyl-DNA phosphodiesterase 1. Nat Commun. 2018 Jan 2;9(1):24. doi: 10.1038/s41467-017-02530-z. PMID:29295983 doi:http://dx.doi.org/10.1038/s41467-017-02530-z
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