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4puq

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Mus Musculus Tdp2 reaction product complex with 5'-phosphorylated RNA/DNA, glycerol, and Mg2+

Structural highlights

4puq is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TYDP2_MOUSE 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 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]

Publication Abstract from PubMed

Eukaryotic type II topoisomerases (Top2alpha and Top2beta) are homodimeric enzymes; essential for altering DNA topology by the formation of normally transient double-strand DNA cleavage. Anticancer drugs (etoposide, doxorubicin, and mitoxantrone), but also Top2 oxidation and DNA helical alterations cause potentially irreversible Top2-DNA cleavage complexes (Top2cc), leading to Top2-linked DNA breaks. Top2cc are the therapeutic mechanism for killing cancer cells. Yet, Top2cc can also generate recombination, translocations and apoptosis in normal cells. The Top2 protein-DNA covalent complexes are excised (in part) by tyrosyl-DNA-phosphodiesterase 2 (TDP2/TTRAP/EAP2/VPg unlinkase). In this study, we show that irreversible Top2cc induced in suicidal substrates are not processed by TDP2 unless they first undergo proteolytic processing or denaturation. We also demonstrate that TDP2 is most efficient when the DNA attached to the tyrosyl is in a single-stranded configuration, and that TDP2 can efficiently remove a tyrosine linked to a single misincorporated ribonucleotide or to polyribonucleotides, which expands the TDP2 catalytic profile with RNA substrates. The 1.6 Angstrom resolution crystal structure of TDP2 bound to a substrate bearing a 5'-ribonucleotide defines a mechanism through which RNA can be accommodated in the TDP2 active site, albeit in a strained conformation.

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2-DNA and -RNA Covalent Complexes by Tyrosyl-DNA-phosphodiesterase 2 (TDP2).,Gao R, Schellenberg MJ, Huang SY, Abdelmalak M, Marchand C, Nitiss KC, Nitiss JL, Williams RS, Pommier Y J Biol Chem. 2014 May 7. pii: jbc.M114.565374. PMID:24808172^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zeng Z, Sharma A, Ju L, Murai J, Umans L, Vermeire L, Pommier Y, Takeda S, Huylebroeck D, Caldecott KW, El-Khamisy SF. TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic Acids Res. 2012 Sep 1;40(17):8371-80. Epub 2012 Jun 26. PMID:22740648 doi:http://dx.doi.org/10.1093/nar/gks622
↑ Gao R, Schellenberg MJ, Huang SY, Abdelmalak M, Marchand C, Nitiss KC, Nitiss JL, Williams RS, Pommier Y. Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2-DNA and -RNA Covalent Complexes by Tyrosyl-DNA-phosphodiesterase 2 (TDP2). J Biol Chem. 2014 May 7. pii: jbc.M114.565374. PMID:24808172 doi:http://dx.doi.org/10.1074/jbc.M114.565374

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4puq"

Categories: Large Structures | Mus musculus | Schellenberg MJ | Williams RS

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4puq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PUQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PUQ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4puq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4puq OCA], [https://pdbe.org/4puq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4puq RCSB], [https://www.ebi.ac.uk/pdbsum/4puq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4puq ProSAT]</span></td></tr>
 </table>

4puq

From Proteopedia

Current revision

Mus Musculus Tdp2 reaction product complex with 5'-phosphorylated RNA/DNA, glycerol, and Mg2+

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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