TOP1

Last updated

DNA topoisomerase 1 is an enzyme that in humans is encoded by the TOP1 gene. It is a DNA , an enzyme that catalyzes the transient breaking and rejoining of a single strand of DNA. Klasa5A Klasa 8

Contents

oztatnia


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, [1] thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. [2]

Mechanism

As reviewed by Champoux, [3] 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 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-terminal 214 amino acids are dispensable for relaxation of supercoiling activity in vitro and there are four nuclear localization signals and sites for 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 Tyr723 is found within the C-terminal domain.

As further summarized by Pommier and by Seol et al., [1] [4] 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' en f the broken strand, 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 verse the phosphotyrosyl bond, e DNA. The nicki

Inhibition

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 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. [5] Irinotecan is especially effective through its 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. [1] One irinotecan or SN-38 molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the TOP1 enzyme. [1] 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. [5] 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. [6]

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, 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 WRN gene in patients with colon cancer. [7] In a 2006 study, 45 patients had colonic tumors with hypermethylated WRN gene promoters (silenced WRN expression), and 43 patients had tumors with unmethylated WRN gene promoters, so that WRN protein expression was high. [7] 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 cancers. [7]

Irinotecan inactivation of TOP1 may be synthetically lethal with deficient expression of DNA repair gene MRE11 . A recent study was carried out with 1,264 patients with stage III colon cancer. [8] The patients were treated with a postoperative weekly adjuvant 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 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. [8]

There are a number of pre-clinical studies indicating synthetic lethality of irinotecan with other genetic or epigenetic DNA repair deficiencies common in cancers. For instance, the DNA repair gene ATM is frequently hypermethylated (silenced) in many cancers (see 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. [9] This indicates synthetic lethality of ATM deficiency with irinotecan-mediated TOP1 deficiency. [9]

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, [10] and appears to have a role in DNA repair. [11] 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. [10]

DNA repair

Exposure of human HeLA cells to UVB irradiation specifically stimulates the formation of covalent complexes between topoisomerase I and DNA. [12] Topoisomerase I appears to have a direct role in nucleotide excision repair, a process that removes UVB-induced, and other, DNA damages. [12]

Interactions

TOP1 has been shown to interact with:

See also

Related Research Articles

DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">ATM serine/threonine kinase</span>

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

<span class="mw-page-title-main">Irinotecan</span> Cancer medication

Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat colon cancer, and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is used with cisplatin. It is given intravenously.

<span class="mw-page-title-main">Werner syndrome helicase</span>

Werner syndrome ATP-dependent helicase, also known as DNA helicase, RecQ-like type 3, is an enzyme that in humans is encoded by the WRN gene. WRN is a member of the RecQ Helicase family. Helicase enzymes generally unwind and separate double-stranded DNA. These activities are necessary before DNA can be copied in preparation for cell division. Helicase enzymes are also critical for making a blueprint of a gene for protein production, a process called transcription. Further evidence suggests that Werner protein plays a critical role in repairing DNA. Overall, this protein helps maintain the structure and integrity of a person's DNA.

<span class="mw-page-title-main">Topotecan</span> Chemical compound

Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer and other cancer types.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Oncogenomics</span> Sub-field of genomics

Oncogenomics is a sub-field of genomics that characterizes cancer-associated genes. It focuses on genomic, epigenomic and transcript alterations in cancer.

<span class="mw-page-title-main">Crosslinking of DNA</span> Crosslinking occurring when various exogenous or endogenous agents react with two nucleotides of DNA

In genetics, crosslinking of DNA occurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them. This crosslink can occur within the same strand (intrastrand) or between opposite strands of double-stranded DNA (interstrand). These adducts interfere with cellular metabolism, such as DNA replication and transcription, triggering cell death. These crosslinks can, however, be repaired through excision or recombination pathways.

<span class="mw-page-title-main">Type I topoisomerase</span>

In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB.

<span class="mw-page-title-main">Nibrin</span> Protein-coding gene in the species Homo sapiens

Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.

<span class="mw-page-title-main">DNA-PKcs</span> Protein-coding gene in the species Homo sapiens

DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids.

<span class="mw-page-title-main">MRE11A</span>

Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the MRE11 gene. The gene has been designated MRE11A to distinguish it from the pseudogene MRE11B that is nowadays named MRE11P1.

<span class="mw-page-title-main">TOP2B</span>

DNA topoisomerase 2-beta is an enzyme that in humans is encoded by the TOP2B gene.

Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism. Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death, whereas a deficiency of only one of these genes does not. In a synthetic lethal genetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differing phenotype, and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

<span class="mw-page-title-main">Belotecan</span>

Belotecan is a drug used in chemotherapy. It is a semi-synthetic camptothecin analogue indicated for small-cell lung cancer and ovarian cancer, approved in South Korea under the trade name Camtobell, presented in 2 mg vials for injection. The drug has been marketed by ChongKunDang Pharmaceuticals since 2003.

<span class="mw-page-title-main">Treatment of cancer</span> Overview of various treatment possibilities for cancer

Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy and synthetic lethality, most commonly as a series of separate treatments. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient. Cancer genome sequencing helps in determining which cancer the patient exactly has for determining the best therapy for the cancer. A number of experimental cancer treatments are also under development. Under current estimates, two in five people will have cancer at some point in their lifetime.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

References

  1. 1 2 3 4 Pommier Y (2013). "Drugging topoisomerases: lessons and challenges". ACS Chem. Biol. 8 (1): 82–95. doi:10.1021/cb300648v. PMC   3549721 . PMID   23259582.
  2. ↑ "Entrez Gene: TOP1 topoisomerase (DNA) I".
  3. ↑ Champoux JJ (2001). "DNA topoisomerases: structure, function, and mechanism". Annu. Rev. Biochem. 70: 369–413. doi:10.1146/annurev.biochem.70.1.369. PMID   11395412.
  4. ↑ Seol Y, Zhang H, Pommier Y, Neuman KC (2012). "A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity". Proc. Natl. Acad. Sci. U.S.A. 109 (40): 16125–30. Bibcode:2012PNAS..10916125S. doi: 10.1073/pnas.1206480109 . PMC   3479559 . PMID   22991469.
  5. 1 2 Liu YQ, Li WQ, Morris-Natschke SL, Qian K, Yang L, Zhu GX, Wu XB, Chen AL, Zhang SY, Nan X, Lee KH (2015). "Perspectives on biologically active camptothecin derivatives". Med Res Rev. 35 (4): 753–89. doi:10.1002/med.21342. PMC   4465867 . PMID   25808858.
  6. ↑ Nagy, Ádám; Pongor, Lőrinc Sándor; Szabó, András; Santarpia, Mariacarmela; Győrffy, Balázs (2017-02-15). "KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer". International Journal of Cancer. 140 (4): 930–937. doi:10.1002/ijc.30509. ISSN   1097-0215. PMC   5299512 . PMID   27859136.
  7. 1 2 3 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 (2006). "Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer". Proc. Natl. Acad. Sci. U.S.A. 103 (23): 8822–7. Bibcode:2006PNAS..103.8822A. doi: 10.1073/pnas.0600645103 . PMC   1466544 . PMID   16723399.
  8. 1 2 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 (2014). "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". PLOS ONE. 9 (10): e108483. Bibcode:2014PLoSO...9j8483P. doi: 10.1371/journal.pone.0108483 . PMC   4195600 . PMID   25310185.
  9. 1 2 Subhash VV, Tan SH, Yeo MS, Yan FL, Peethala PC, Liem N, Krishnan V, Yong WP (2016). "ATM expression predicts Veliparib and Irinotecan sensitivity in gastric cancer by mediating P53 independent regulation of cell cycle and apoptosis". Mol. Cancer Ther. 15 (12): 3087–3096. doi: 10.1158/1535-7163.MCT-15-1002 . PMID   27638859.
  10. 1 2 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 (2013). "Identification of cetrimonium bromide and irinotecan as compounds with synthetic lethality against NDRG1 deficient prostate cancer cells". Cancer Biol. Ther. 14 (5): 401–10. doi:10.4161/cbt.23759. PMC   3672184 . PMID   23377825.
  11. ↑ Dominick G, Bowman J, Li X, Miller RA, Garcia GG (2016). "mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice". Aging Cell. 16 (1): 52–60. doi:10.1111/acel.12525. PMC   5242303 . PMID   27618784.
  12. 1 2 Subramanian, D.; Rosenstein, B. S.; Muller, M. T. (1998). "Ultraviolet-induced DNA damage stimulates topoisomerase I-DNA complex formation in vivo: Possible relationship with DNA repair". Cancer Research. 58 (5): 976–84. PMID   9500459.
  13. ↑ Labourier E, Rossi F, Gallouzi IE, Allemand E, Divita G, Tazi J (Jun 1998). "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". Nucleic Acids Research. 26 (12): 2955–62. doi:10.1093/nar/26.12.2955. PMC   147637 . PMID   9611241.
  14. ↑ Andersen FF, Tange TØ, Sinnathamby T, Olesen JR, Andersen KE, Westergaard O, Kjems J, Knudsen BR (Sep 2002). "The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation". Journal of Molecular Biology. 322 (4): 677–86. doi:10.1016/s0022-2836(02)00815-x. PMID   12270705.
  15. 1 2 Xu L, Yang L, Hashimoto K, Anderson M, Kohlhagen G, Pommier Y, D'Arpa P (2002). "Characterization of BTBD1 and BTBD2, two similar BTB-domain-containing Kelch-like proteins that interact with Topoisomerase I". BMC Genomics. 3: 1. doi:10.1186/1471-2164-3-1. PMC   64781 . PMID   11818025.
  16. ↑ Haluska P, Saleem A, Edwards TK, Rubin EH (Apr 1998). "Interaction between the N-terminus of human topoisomerase I and SV40 large T antigen". Nucleic Acids Research. 26 (7): 1841–7. doi:10.1093/nar/26.7.1841. PMC   147454 . PMID   9512561.
  17. ↑ Bharti AK, Olson MO, Kufe DW, Rubin EH (Jan 1996). "Identification of a nucleolin binding site in human topoisomerase I". The Journal of Biological Chemistry. 271 (4): 1993–7. doi: 10.1074/jbc.271.4.1993 . PMID   8567649.
  18. ↑ Gobert C, Skladanowski A, Larsen AK (Aug 1999). "The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53". Proceedings of the National Academy of Sciences of the United States of America. 96 (18): 10355–60. Bibcode:1999PNAS...9610355G. doi: 10.1073/pnas.96.18.10355 . PMC   17892 . PMID   10468612.
  19. ↑ Mao Y, Mehl IR, Muller MT (Feb 2002). "Subnuclear distribution of topoisomerase I is linked to ongoing transcription and p53 status". Proceedings of the National Academy of Sciences of the United States of America. 99 (3): 1235–40. Bibcode:2002PNAS...99.1235M. doi: 10.1073/pnas.022631899 . PMC   122173 . PMID   11805286.
  20. ↑ Mao Y, Sun M, Desai SD, Liu LF (Apr 2000). "SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage". Proceedings of the National Academy of Sciences of the United States of America. 97 (8): 4046–51. Bibcode:2000PNAS...97.4046M. doi: 10.1073/pnas.080536597 . PMC   18143 . PMID   10759568.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.