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topoisomerase-1 (TOP1)

Function: - conversion of one topological isomer of DNA to another - catalyzes ATP-independent breakage of single-stranded DNA, followed by passage & rejoining - transiently breaks a DNA strand & forms a covalent bond between the active-site Tyr & the 3'phosphate of the broken DNA strand; the strand is subsequently re-ligated by nucleophilic attack of the 5'hydroxyl on this phosphodiester bond - under certain conditions, nucleophilic attack of the 5'hydroxyl does not occur & the topoisomerase 1 forms a stalled covalent complex with the DNA; efficient repair of these stalled complexes is facilitated by tyrosyl-DNA phosphodiesterase 1 - cofactor for activator-dependent transcription by RNA polymerase 2 (identical to transcriptional cofactor termed PC3) - eukaryotic topoisomerase 1 & topoisomerase 1 can relax both negative & positive supercoils, whereas prokaryotic enzymes relax only negative supercoils - specifically inhibited by camptothecin (CPT), a plant alkaloid with antitumor activity Structure: - monomer - belongs to the eukaryotic type I topoisomerase family Pathology: - chromosomal translocation t(11;20)(p15;q11) involving TOP1 with NUP98 is found in a form of therapy-related myelodysplastic syndrome - topoisomerase 1 acts as a positive regulator of RNA polymerase II transcriptional activity at pathogen- induced genes [3] (see topoisomerase-1 inhibitor)

Interactions

molecular events

Related

Scl-70 antigen tyrosyl-DNA phosphodiesterase 1; tyr-DNA phosphodiesterase 1 (TDP1)

General

topoisomerase

Properties

SIZE: MW = 91 kD entity length = 765 aa COMPARTMENT: cell nucleus MOTIF: lysine residue {191-197} (7) active site MOTIF: tyrosine residue S/T phosphorylation site tyrosine residue {Y723}

Database Correlations

OMIM 126420 MORBIDMAP 126420 UniProt P11387 PFAM correlations Kegg hsa:7150 ENZYME 5.99.1.2

References

  1. Kretzschmar M et al Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11508-12. PMID: 8265582
  2. Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 1019 (MW)
  3. Atlas of genetics & cytogenetics in oncology & Haematology http://atlasgeneticsoncology.org/genes/TOP1ID320ch20q11.html
  4. UniProt :accession P11387
  5. Rialdi A et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 2016 May 27; 352:aad7993 PMID: 27127234