Function: Type IB topoisomerase forms a protein clamp around the DNA duplex and creates a transient nick that permits removal of supercoils. Using real-time single-molecule observation, Koster et al. (2005) demonstrated that TOPIB releases supercoils by a swivel mechanism that involves friction between the rotating DNA and the enzyme cavity, i.e., the DNA does not freely rotate. Unlike a nicking enzyme, TOPIB did not release all the supercoils at once but rather in multiple steps. The number of supercoils removed per step followed an exponential distribution. The enzyme was found to be torque-sensitive, as the mean number of supercoils per step increased with the torque stored in the DNA. Koster et al. (2005) proposed a model for topoisomerization in which the torque drives the DNA rotation over a rugged periodic energy landscape in which the topoisomerase has a small but quantifiable probability to religate the DNA once per turn.

Source Reference: [PubMed ID: 21086148] Chou SM, Huang TH, Chen HC, Li TK, Calcium-induced cleavage of DNA topoisomerase I involves the cytoplasmic-nuclear shuttling of calpain 2. Cell Mol Life Sci. 2011 Aug;68(16):2769-84. doi: 10.1007/s00018-010-0591-4. Epub

Summary

Top-ranked sequences

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188
            ||||||||||||||||||||||||||||||#||||||||||||||||||||||||||||||
Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188
            ||||||||||||||||||||||||||||||#||||||||||||||||||||||||||||||
Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188
            |||||||||||||||||||||||||||| |#|||||||||||||||+||||||||||||||
Sbjct   131 PKEDIKPLKRPRDEDDADYKPKKIKTEDIK#KEKKRKLEEEEDGKLRKPKNKDKDKKVPEP  190

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188
            |||||||||||||||||||||||||||| |#||||||||||||||||||||||||||| ||
Sbjct   131 PKEDIKPLKRPRDEDDADYKPKKIKTEDIK#KEKKRKLEEEEDGKLKKPKNKDKDKKVAEP  190

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEE  169
            |||| |||||||++|||||||||||||| |#| |||| ||||
Sbjct   133 PKEDSKPLKRPREDDDADYKPKKIKTEDVK#KAKKRKQEEEE  173

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDG  171
            |||||||||||||||||||||||||||| |#|||||||||||||
Sbjct   131 PKEDIKPLKRPRDEDDADYKPKKIKTEDIK#KEKKRKLEEEEDG  173

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNKDKDKKVPEP  188
            |||||||||| ||||||||||||||||| |#|||||| |||||||||||||||||||| ||
Sbjct   131 PKEDIKPLKRLRDEDDADYKPKKIKTEDIK#KEKKRKSEEEEDGKLKKPKNKDKDKKVAEP  190

Query   129 PKEDIKPLKRPRDEDDADYKP-KKIKTEDTK#KEKKRKLEEEEDGKL--KKPKNKDKDKKV  185
            ||||||||||||+|||||||| |||| || |#|||||||||||||||   | | |+|||||
Sbjct   365 PKEDIKPLKRPREEDDADYKPNKKIKAEDIK#KEKKRKLEEEEDGKLKKPKNKEKEKDKKV  424

Query   186 PEP  188
            |||
Query   186 PEP  188

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEE  168
            |||+ | +|||| ||| ||||||||+|| |#| |||| |||
Sbjct   192 PKEN-KAMKRPR-EDDEDYKPKKIKSEDDK#KGKKRKQEEE  229

Query   129 PKEDIKPLKRPRDEDDADYKPKKIKTEDTK#KEKKRKLEEEEDGKLKKPKNK  179
            || | | ||| ||+|| + ||||||||+ |#| ||||  + || |  | |||
Sbjct   104 PKND-KSLKRERDDDDYEIKPKKIKTENDK#KAKKRK-PQVEDIKTVKTKNK  152

Summary

Top-ranked sequences

Query   154 TEDTKKEKKRKLEEEEDGKLKKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  213
            ||||||||||||||||||||||||||||||#||||||||||||||||||||||||||||||
Query   154 TEDTKKEKKRKLEEEEDGKLKKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  213

Query   154 TEDTKKEKKRKLEEEEDGKLKKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  213
            ||||||||||||||||||||||||||||||#||||||||||||||||||||||||||||||
Query   154 TEDTKKEKKRKLEEEEDGKLKKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  213

Query   154 TEDTKKEKKRKLEEEEDGKLKKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  213
            ||| ||||||||||||||||+|||||||||#||||||||||||||||||||||||||||||
Sbjct   156 TEDIKKEKKRKLEEEEDGKLRKPKNKDKDK#KVPEPDNKKKKPKKEEEQKWKWWEEERYPE  215

[PubMed ID: 24097068] ... Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkila K, Hypponen E, Isaacs A, Jackson AU, Johansson A, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikainen LP, Magnusson PK, Mangino M, Mihailov E, Montasser ME, Muller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS, Doring A, Elliott P, Epstein SE, Eyjolfsson GI, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimaki T, Lin SY, Lindstrom J, Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell BD, Muller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stancakova A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YD, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrieres J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Jarvelin MR, Jula A, Kahonen M, Kaprio J, Kesaniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, Marz W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njolstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BH, Ordovas JM, Boerwinkle E, Palmer CN, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Kathiresan S, Mohlke KL, Ingelsson E, Abecasis GR, Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013 Nov;45(11):1274-83. doi: 10.1038/ng.2797. Epub 2013 Oct 6.

[PubMed ID: 24069881] ... Miao Z, Zhu L, Dong G, Zhuang C, Wu Y, Wang S, Guo Z, Liu Y, Wu S, Zhu S, Fang K, Yao J, Li J, Sheng C, Zhang W, A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors. J Med Chem. 2013 Oct 24;56(20):7902-10. doi: 10.1021/jm400906z. Epub 2013 Oct 9.

[PubMed ID: 24123038] ... Negri FV, Azzoni C, Bottarelli L, Campanini N, Mandolesi A, Wotherspoon A, Cunningham D, Scartozzi M, Cascinu S, Tinelli C, Silini EM, Ardizzoni A, Thymidylate synthase, topoisomerase-1 and microsatellite instability: relationship with outcome in mucinous colorectal cancer treated with fluorouracil. Anticancer Res. 2013 Oct;33(10):4611-7.

[PubMed ID: 24013388] ... Afriat R, Horowitz S, Priel E, Mycoplasma fermentans inhibits the activity of cellular DNA topoisomerase I by activation of PARP1 and alters the efficacy of its anti-cancer inhibitor. PLoS One. 2013 Aug 27;8(8):e72377. doi: 10.1371/journal.pone.0072377. eCollection

[PubMed ID: 17081983] ... Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M, Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006 Nov 3;127(3):635-48.

[PubMed ID: 12149243] ... Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D'Arpa P, Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin. J Biol Chem. 2002 Oct 18;277(42):40020-6. Epub 2002 Jul 30.

[PubMed ID: 9933635] ... Samejima K, Svingen PA, Basi GS, Kottke T, Mesner PW Jr, Stewart L, Durrieu F, Poirier GG, Alnemri ES, Champoux JJ, Kaufmann SH, Earnshaw WC, Caspase-mediated cleavage of DNA topoisomerase I at unconventional sites during apoptosis. J Biol Chem. 1999 Feb 12;274(7):4335-40.

[PubMed ID: 1332703] ... Kubota N, Kanzawa F, Nishio K, Takeda Y, Ohmori T, Fujiwara Y, Terashima Y, Saijo N, Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line. Biochem Biophys Res Commun. 1992 Oct 30;188(2):571-7.

[PubMed ID: 1339303] ... Zhou BS, Beidler DR, Cheng YC, Identification of antisense RNA transcripts from a human DNA topoisomerase I pseudogene. Cancer Res. 1992 Aug 1;52(15):4280-5.

[PubMed ID: 1851751] ... Kunze N, Yang GC, Dolberg M, Sundarp R, Knippers R, Richter A, Structure of the human type I DNA topoisomerase gene. J Biol Chem. 1991 May 25;266(15):9610-6.

[PubMed ID: 1849260] ... Tamura H, Kohchi C, Yamada R, Ikeda T, Koiwai O, Patterson E, Keene JD, Okada K, Kjeldsen E, Nishikawa K, et al., Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites. Nucleic Acids Res. 1991 Jan 11;19(1):69-75.

[PubMed ID: 2174357] ... Priel E, Showalter SD, Roberts M, Oroszlan S, Segal S, Aboud M, Blair DG, Topoisomerase I activity associated with human immunodeficiency virus (HIV) particles and equine infectious anemia virus core. EMBO J. 1990 Dec;9(12):4167-72.