| Structural highlights
Disease
[TYDP2_HUMAN] Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
Function
[TYDP2_HUMAN] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
TDP2 is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II. TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for HTS-screening. We have gone on to determine crystal structures of these compounds bound to a 'humanised' form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2.
Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.,Hornyak P, Askwith T, Walker S, Komulainen E, Paradowski M, Pennicott LE, Bartlett EJ, Brissett NC, Raoof A, Watson M, Jordan AM, Ogilvie DJ, Ward SE, Atack JR, Pearl LH, Caldecott KW, Oliver AW Biochem J. 2016 Apr 20. pii: BCJ20160180. PMID:27099339[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cortes Ledesma F, El Khamisy SF, Zuma MC, Osborn K, Caldecott KW. A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature. 2009 Oct 1;461(7264):674-8. doi: 10.1038/nature08444. PMID:19794497 doi:http://dx.doi.org/10.1038/nature08444
- ↑ Zeng Z, Cortes-Ledesma F, El Khamisy SF, Caldecott KW. TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in vertebrate cells and is critical for cellular resistance to topoisomerase II-induced DNA damage. J Biol Chem. 2011 Jan 7;286(1):403-9. doi: 10.1074/jbc.M110.181016. Epub 2010 Oct, 28. PMID:21030584 doi:http://dx.doi.org/10.1074/jbc.M110.181016
- ↑ Vilotti S, Biagioli M, Foti R, Dal Ferro M, Lavina ZS, Collavin L, Del Sal G, Zucchelli S, Gustincich S. The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition. Cell Death Differ. 2012 Mar;19(3):488-500. doi: 10.1038/cdd.2011.118. Epub 2011, Sep 16. PMID:21921940 doi:http://dx.doi.org/10.1038/cdd.2011.118
- ↑ Varady G, Sarkadi B, Fatyol K. TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-beta signaling pathway. PLoS One. 2011;6(9):e25548. doi: 10.1371/journal.pone.0025548. Epub 2011 Sep 27. PMID:21980489 doi:http://dx.doi.org/10.1371/journal.pone.0025548
- ↑ Adhikari S, Karmahapatra SK, Karve TM, Bandyopadhyay S, Woodrick J, Manthena PV, Glasgow E, Byers S, Saha T, Uren A. Characterization of magnesium requirement of human 5'-tyrosyl DNA phosphodiesterase mediated reaction. BMC Res Notes. 2012 Mar 9;5:134. doi: 10.1186/1756-0500-5-134. PMID:22405347 doi:http://dx.doi.org/10.1186/1756-0500-5-134
- ↑ 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
- ↑ Virgen-Slane R, Rozovics JM, Fitzgerald KD, Ngo T, Chou W, van der Heden van Noort GJ, Filippov DV, Gershon PD, Semler BL. An RNA virus hijacks an incognito function of a DNA repair enzyme. Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14634-9. doi:, 10.1073/pnas.1208096109. Epub 2012 Aug 20. PMID:22908287 doi:http://dx.doi.org/10.1073/pnas.1208096109
- ↑ Hornyak P, Askwith T, Walker S, Komulainen E, Paradowski M, Pennicott LE, Bartlett EJ, Brissett NC, Raoof A, Watson M, Jordan AM, Ogilvie DJ, Ward SE, Atack JR, Pearl LH, Caldecott KW, Oliver AW. Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochem J. 2016 Apr 20. pii: BCJ20160180. PMID:27099339 doi:http://dx.doi.org/10.1042/BCJ20160180
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