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{{short description|DNA topoisomerase enzyme}}
{{Infobox_gene}}
'''DNA topoisomerase 1''' is an [[enzyme]] that in humans is encoded by the ''TOP1'' [[gene]]. It is a [[DNA topoisomerase]], an enzyme that catalyzes the transient breaking and rejoining of a single strand of [[DNA]].

== Function ==

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which lets the broken strand rotate around the intact strand,<ref name=Pommier>{{cite journal |vauthors=Pommier Y |title=Drugging topoisomerases: lessons and challenges |journal=ACS Chem. Biol. |volume=8 |issue=1 |pages=82–95 |year=2013 |pmid=23259582 |pmc=3549721 |doi=10.1021/cb300648v }}</ref> thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22.<ref>{{cite web | title = Entrez Gene: TOP1 topoisomerase (DNA) I| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7150}}</ref>

==Mechanism==

As reviewed by Champoux,<ref name="pmid11395412">{{cite journal |vauthors=Champoux JJ |title=DNA topoisomerases: structure, function, and mechanism |journal=Annu. Rev. Biochem. |volume=70 |pages=369–413 |year=2001 |pmid=11395412 |doi=10.1146/annurev.biochem.70.1.369 }}</ref> the type IB topoisomerases, including TOP1, form a covalent intermediate in which the active site tyrosine becomes attached to the 3' phosphate end of the cleaved strand rather than the 5' phosphate end.

The eukaryotic [[Type I topoisomerase|topoisomerases I]] were found to nick the DNA with a preference for a sequence of nucleotides that extends from positions -4 to -1 from the nick.  The preferred nucleotides in the strand to be cut are 5'-(A/T)(G/C)(A/T)T-3' with the enzyme covalently attached to the -1 T residue, though sometimes a C residue is found at the -1 position.

The TOP1 protein of humans has been subdivided into four regions. The [[N-terminus|N-terminal]] 214 amino acids are dispensable for relaxation of [[DNA supercoil|supercoiling]] activity ''[[in vitro]]'' and there are four [[Nuclear localization sequence|nuclear localization signals]] and sites for [[Protein–protein interaction|interaction with other cellular proteins]] within the N-terminal domain.  The N-terminal domain is followed by a highly conserved, 421 amino acid core domain containing all of the catalytic residues except the active site [[tyrosine]].  This is followed by a poorly conserved linker domain of 77 amino acids.  Finally there is a 53 amino acid C-terminal domain.  The [[active site]] [[Tyrosine|Tyr]]723 is found within the C-terminal domain.

As further summarized by Pommier and by Seol et al.,<ref name=Pommier /><ref name="pmid22991469">{{cite journal |vauthors=Seol Y, Zhang H, Pommier Y, Neuman KC |title=A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=109 |issue=40 |pages=16125–30 |year=2012 |pmid=22991469 |pmc=3479559 |doi=10.1073/pnas.1206480109 |bibcode=2012PNAS..10916125S |doi-access=free }}</ref>  TOP1 breaks the DNA by a [[transesterification]] reaction using the active site tyrosine as the [[nucleophile]] that attacks the DNA phosphodiester backbone.  After the TOP1 covalently attaches to the 3' end of the broken strand, [[DNA supercoil|supercoiling]] of the DNA is relaxed by controlled rotation of DNA about the intact strand.  Then the 5' hydroxyl end of the broken DNA strand can reverse the phosphotyrosyl bond, enabling the release of TOP1 and [[Ligation (molecular biology)|religation]] of the DNA.  The nicking and closing reactions are fast, and about 100 cycles can occur per second.

==Inhibition==
{{main article|Topoisomerase inhibitor}}

The briefly attached, covalently bonded TOP1-DNA structure at the 3' end of a cleaved DNA single strand is called a TOP1-DNA cleavage complex, or TOP1cc.  The TOP1cc is a specific target of TOP1 [[Topoisomerase inhibitor|inhibitors]].  One of the first inhibitors shown to target TOP1 is [[irinotecan]].  Irinotecan is an analogue of the cytotoxic natural alkaloid [[camptothecin]], obtained from the Chinese tree ''Camptotheca acuminata''.<ref name=Liu>{{cite journal |vauthors=Liu YQ, Li WQ, Morris-Natschke SL, Qian K, Yang L, Zhu GX, Wu XB, Chen AL, Zhang SY, Nan X, Lee KH |title=Perspectives on biologically active camptothecin derivatives |journal=Med Res Rev |volume=35 |issue=4 |pages=753–89 |year=2015 |pmid=25808858 |pmc=4465867 |doi=10.1002/med.21342 }}</ref>  Irinotecan is especially effective through its [[Active metabolite|metabolic]] product [[SN-38]].  Irinotecan and [[SN-38]] act by trapping a subset of TOP1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence.<ref name="Pommier"/>  One irinotecan or SN-38 molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the TOP1 enzyme.<ref name=Pommier />  The article [[Camptothecin]] lists other analogues of camptothecin and the article [[Topoisomerase inhibitor]] lists other compounds which inhibit TOP1.

==Cancer==

Since 1985, TOP1 has been known as a target for the treatment of human cancers.<ref name=Liu /> Camptothecin analogues irinotecan and [[topotecan]], which inhibit TOP1, are among the most effective FDA-approved anticancer chemotherapeutic agents used in clinical practice. Higher expression of TOP1 in KRAS mutant non-small cell lung cancer and correlation to survival suggests that TOP1 inhibitors might have increased benefit when administered to treat patients with a KRAS mutant tumor.<ref>{{Cite journal|last1=Nagy|first1=Ádám|last2=Pongor|first2=Lőrinc Sándor|last3=Szabó|first3=András|last4=Santarpia|first4=Mariacarmela|last5=Győrffy|first5=Balázs|date=2017-02-15|title=KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer|journal=International Journal of Cancer|volume=140|issue=4|pages=930–937|doi=10.1002/ijc.30509|issn=1097-0215|pmc=5299512|pmid=27859136}}</ref>

===Synthetic lethality===

[[Synthetic lethality]] arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through [[mutation]], [[Cancer epigenetics|epigenetic alteration]] or by inhibition of a gene's expression.

Irinotecan inactivation of TOP1 appears to be synthetically lethal in combination with deficiencies in expression of some specific DNA repair genes.

Irinotecan inactivation of TOP1 was synthetically lethal with deficient expression of the DNA repair [[Werner syndrome ATP-dependent helicase|''WRN'']] gene in patients with colon cancer.<ref name=Agrelo>{{cite journal |vauthors=Agrelo R, Cheng WH, Setien F, Ropero S, Espada J, Fraga MF, Herranz M, Paz MF, Sanchez-Cespedes M, Artiga MJ, Guerrero D, Castells A, von Kobbe C, Bohr VA, Esteller M |title=Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=23 |pages=8822–7 |year=2006 |pmid=16723399 |pmc=1466544 |doi=10.1073/pnas.0600645103 |bibcode=2006PNAS..103.8822A |doi-access=free }}</ref>  In a 2006 study, 45 patients had colonic tumors with [[DNA methylation|hypermethylated]] ''WRN'' gene [[Promoter (genetics)|promoters]] (silenced ''WRN'' expression), and 43 patients had tumors with unmethylated ''WRN'' gene promoters, so that WRN protein expression was high.<ref name=Agrelo />  Irinotecan was more strongly beneficial for patients with hypermethylated ''WRN'' promoters (39.4 months survival) than for those with unmethylated ''WRN'' promoters (20.7 months survival).  The ''WRN'' gene promoter is hypermethylated in about 38% of [[colorectal cancer]]s.<ref name=Agrelo />

Irinotecan inactivation of TOP1 may be synthetically lethal with deficient expression of DNA repair gene ''[[MRE11A|MRE11]]''.  A recent study was carried out with 1,264 patients with stage III colon cancer.<ref name=Pavelitz>{{cite journal |vauthors=Pavelitz T, Renfro L, Foster NR, Caracol A, Welsch P, Lao VV, Grady WB, Niedzwiecki D, Saltz LB, Bertagnolli MM, Goldberg RM, Rabinovitch PS, Emond M, Monnat RJ, Maizels N |title=MRE11-deficiency associated with improved long-term disease free survival and overall survival in a subset of stage III colon cancer patients in randomized CALGB 89803 trial |journal=PLOS ONE |volume=9 |issue=10 |pages=e108483 |year=2014 |pmid=25310185 |pmc=4195600 |doi=10.1371/journal.pone.0108483 |bibcode=2014PLoSO...9j8483P |doi-access=free }}</ref>  The patients were treated with a postoperative weekly [[Adjuvant therapy|adjuvant]] [[Bolus (medicine)|bolus]] of 5-fluorouracil/leucovorin (FU/LV) or else with irinotecan+FU/LV and were followed up for 8 years.  Eleven percent of the tumors were deficient for DNA repair enzyme [[MRE11A|MRE11]] due to a deletion of a string of thymidines in the DNA sequence of the ''MRE11'' gene.  The addition of irinotecan to FU/LV in the treatment protocol resulted in ''MRE11''-deficient patients having better long-term disease free survival than patients with wild-type ''MRE11'' (though the effect was small), indicating some degree of synthetic lethality between irinotecan-induced TOP1 inactivation and ''MRE11'' deficiency.<ref name=Pavelitz />

There are a number of [[Phases of clinical research#Phases|pre-clinical]] studies indicating synthetic lethality of irinotecan with other genetic or [[Cancer epigenetics|epigenetic]] DNA repair deficiencies common in cancers.  For instance, the DNA repair gene [[ATM serine/threonine kinase|''ATM'']] is frequently [[DNA methylation in cancer|hypermethylated]] (silenced) in many cancers (see [[ATM serine/threonine kinase#Frequent epigenetic deficiencies of ATM in cancers|hypermethylation of ATM in cancers]]).  A 2016 study showed that low expression of the ATM protein in gastric cancer cells ''in vitro'' and in a mouse model caused increased sensitivity to inactivation by irinotecan compared to cells with high expression of ATM.<ref name=Subhash>{{cite journal |vauthors=Subhash VV, Tan SH, Yeo MS, Yan FL, Peethala PC, Liem N, Krishnan V, Yong WP |title=ATM expression predicts Veliparib and Irinotecan sensitivity in gastric cancer by mediating P53 independent regulation of cell cycle and apoptosis |journal=Mol. Cancer Ther. |volume= 15|issue= 12|pages= 3087–3096|year=2016 |pmid=27638859 |doi=10.1158/1535-7163.MCT-15-1002 |doi-access=free }}</ref>  This indicates synthetic lethality of ATM deficiency with irinotecan-mediated TOP1 deficiency.<ref name=Subhash />

Another pre-clinical effort was a screening study to find a compound that would be synthetically lethal with a deficiency of N-myc downstream regulated gene 1 (''[[NDRG1]]'') expression.  ''NDRG1'' is a metastasis-suppressor gene in prostate cancer,<ref name=Wissing>{{cite journal |vauthors=Wissing MD, Mendonca J, Kim E, Kim E, Shim JS, Kaelber NS, Kant H, Hammers H, Commes T, Van Diest PJ, Liu JO, Kachhap SK |title=Identification of cetrimonium bromide and irinotecan as compounds with synthetic lethality against NDRG1 deficient prostate cancer cells |journal=Cancer Biol. Ther. |volume=14 |issue=5 |pages=401–10 |year=2013 |pmid=23377825 |pmc=3672184 |doi=10.4161/cbt.23759 }}</ref> and appears to have a role in DNA repair.<ref name="pmid27618784">{{cite journal |vauthors=Dominick G, Bowman J, Li X, Miller RA, Garcia GG |title=mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice |journal=Aging Cell |volume= 16|issue= 1|pages= 52–60|year=2016 |pmid=27618784 |doi=10.1111/acel.12525 |pmc=5242303}}</ref>  Screening of 3360 compounds revealed that irinotecan-mediated TOP1 deficiency (and one other compound, cetrimonium bromide) exhibit synthetic lethality with NDRG1 deficiency in prostate cancer cells.<ref name=Wissing />

==DNA repair== 

Exposure of human HeLA cells to [[ultraviolet|UVB]] irradiation specifically stimulates the formation of covalent complexes between topoisomerase I and [[DNA]].<ref name = Subramanian1998>{{cite journal|pmid=9500459|year=1998|last1=Subramanian|first1=D.|last2=Rosenstein|first2=B. S.|last3=Muller|first3=M. T.|title=Ultraviolet-induced DNA damage stimulates topoisomerase I-DNA complex formation in vivo: Possible relationship with DNA repair|journal=Cancer Research|volume=58|issue=5|pages=976–84}}</ref>   Topoisomerase I appears to have a direct role in [[nucleotide excision repair]], a  process that removes UVB-induced, and other, DNA damages.<ref name = Subramanian1998/>

== Interactions ==

TOP1 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[ASF/SF2]],<ref name = pmid9611241>{{cite journal | vauthors = Labourier E, Rossi F, Gallouzi IE, Allemand E, Divita G, Tazi J | title = Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor | journal = Nucleic Acids Research | volume = 26 | issue = 12 | pages = 2955–62 | date = Jun 1998 | pmid = 9611241 | pmc = 147637 | doi =  10.1093/nar/26.12.2955}}</ref><ref name = pmid12270705>{{cite journal | vauthors = Andersen FF, Tange TØ, Sinnathamby T, Olesen JR, Andersen KE, Westergaard O, Kjems J, Knudsen BR | title = The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation | journal = Journal of Molecular Biology | volume = 322 | issue = 4 | pages = 677–86 | date = Sep 2002 | pmid = 12270705 | doi =  10.1016/s0022-2836(02)00815-x}}</ref> 
* [[BTBD1]],<ref name = pmid11818025>{{cite journal | vauthors = Xu L, Yang L, Hashimoto K, Anderson M, Kohlhagen G, Pommier Y, D'Arpa P | title = Characterization of BTBD1 and BTBD2, two similar BTB-domain-containing Kelch-like proteins that interact with Topoisomerase I | journal = BMC Genomics | volume = 3 | pages = 1 | pmid = 11818025 | pmc = 64781 | doi = 10.1186/1471-2164-3-1| year=2002 | doi-access = free }}</ref> 
* [[BTBD2]],<ref name = pmid11818025/> 
* [[Nucleolin]],<ref name = pmid9512561>{{cite journal | vauthors = Haluska P, Saleem A, Edwards TK, Rubin EH | title = Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen | journal = Nucleic Acids Research | volume = 26 | issue = 7 | pages = 1841–7 | date = Apr 1998 | pmid = 9512561 | pmc = 147454 | doi =  10.1093/nar/26.7.1841}}</ref><ref name = pmid8567649>{{cite journal | vauthors = Bharti AK, Olson MO, Kufe DW, Rubin EH | title = Identification of a nucleolin binding site in human topoisomerase I | journal = The Journal of Biological Chemistry | volume = 271 | issue = 4 | pages = 1993–7 | date = Jan 1996 | pmid = 8567649 | doi =  10.1074/jbc.271.4.1993| doi-access = free }}</ref> 
* [[P53]],<ref name = pmid10468612>{{cite journal | vauthors = Gobert C, Skladanowski A, Larsen AK | title = The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 18 | pages = 10355–60 | date = Aug 1999 | pmid = 10468612 | pmc = 17892 | doi =  10.1073/pnas.96.18.10355| bibcode = 1999PNAS...9610355G | doi-access = free }}</ref><ref name = pmid11805286>{{cite journal | vauthors = Mao Y, Mehl IR, Muller MT | title = Subnuclear distribution of topoisomerase I is linked to ongoing transcription and p53 status | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 3 | pages = 1235–40 | date = Feb 2002 | pmid = 11805286 | pmc = 122173 | doi = 10.1073/pnas.022631899 | bibcode = 2002PNAS...99.1235M | doi-access = free }}</ref>  and
* [[UBE2I]].<ref name = pmid10759568>{{cite journal|author4-link=Leroy Liu  | vauthors = Mao Y, Sun M, Desai SD, Liu LF | title = SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 8 | pages = 4046–51 | date = Apr 2000 | pmid = 10759568 | pmc = 18143 | doi = 10.1073/pnas.080536597 | bibcode = 2000PNAS...97.4046M | doi-access = free }}</ref>
{{Div col end}}

== See also ==
* [[Type I topoisomerase]]
* [[Topoisomerase]]

== References ==
{{reflist|33em}}

== External links ==
*{{PDBe-KB2|P11387|DNA topoisomerase 1}}

{{PDB Gallery|geneid=7150}}