Other entities represented in this entry:
HGNC Approved Gene Symbol: TOP1
Cytogenetic location: 20q12 Genomic coordinates (GRCh38): 20:41,028,822-41,124,487 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q12 | DNA topoisomerase I, camptothecin-resistant | 3 |
DNA topoisomerases I and II (126430) catalyze the breaking and rejoining of DNA strands in a way that allows the strands to pass through one another, thus altering the topology of DNA. Type I topoisomerases (EC 5.99.1.2) break a single DNA strand, whereas the type II enzymes break 2 strands of duplex DNA. Several lines of evidence suggest that topoisomerase I normally functions during transcription (summary by D'Arpa et al., 1988).
D'Arpa et al. (1988) reported the cDNA cloning of human topoisomerase I.
Independently, Juan et al. (1988) isolated cDNA clones of the human TOP1 gene by immunochemical screening of lambda phage libraries expressing human cDNA segments, using rabbit antibodies raised against purified HeLa DNA topoisomerase I.
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.
Using a combination of proteomics, cytology, and functional analysis in C. elegans, Chu et al. (2006) reduced 1,099 proteins copurified with spermatogenic chromatin to 132 proteins for functional analysis. This strategy to find fertility factors conserved from C. elegans to mammals achieved its goal: of mouse gene knockouts corresponding to nematode proteins, 37% (7 of 19) cause male sterility. This list includes PPP1CC (176914), H2AX (601772), SON (182465), TOP1, DDX4 (605281), DBY (400010), and CENPC (117141).
Using short hairpin RNAs, Humbert et al. (2009) found that knockdown of TOP1 increased the replicative potential of normal human diploid fibroblasts concomitant with reduced expression of senescence markers and diminished DNA damage response. Conversely, TOP1 overexpression induced growth arrest, appearance of a senescence marker, and activation of the DNA damage response. Western blot analysis revealed that knockdown of TOP1 was associated with reductions in phosphorylated ATM (607585), phosphorylated p53 (TP53; 191170), and total p53 and p21 (CDKN1A; 116899) proteins. Humbert et al. (2009) concluded that TOP1 controls cellular senescence via the DNA damage-p53 pathway.
RNase H2 is specialized to remove single ribonucleotides (ribonucleoside monophosphates, or rNMPs) from duplex DNA, and its absence in budding yeast has been associated with the accumulation of deletions within short tandem repeats. Kim et al. (2011) demonstrated that rNMP-associated deletion formation requires the activity of Top1, a topoisomerase that relaxes supercoils by reversibly nicking duplex DNA. The reported studies extended the role of Top1 to include the processing of rNMPs in genomic DNA into irreversible single-strand breaks, an activity that can have distinct mutagenic consequences and may be relevant to human disease.
King et al. (2013) found that topotecan, a TOP1 inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kb. Expression of long genes is also reduced after knockdown of Top1 or Top2b (126431) in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genomewide in neurons, King et al. (2013) found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence autism spectrum disorder (209850) candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. King et al. (2013) concluded that chemicals and genetic mutations that impair topoisomerases could commonly contribute to autism spectrum disorders and other neurodevelopmental disorders.
Using a genomewide screen in murine induced pluripotent stem cells, Dejosez et al. (2013) identified a network of genes, centered on p53, topoisomerase, and olfactory receptors (see 164342), whose downregulation caused the cells to replace wildtype cells in vitro and in the mouse embryo, but without perturbing normal development. Dejosez et al. (2013) suggested that these genes appear to fulfill an unexpected role in fostering cell cooperation.
By immunoprecipitation and mass spectrometry analyses in HEK293 cells, Fielden et al. (2020) identified p97 (601023) as an interacting partner of TOP1. By interacting with TOP1, p97 functioned as a modulator of TOP1 cleavage complex (TOP1cc) repair, as p97 ATPase activity was needed to counteract TOP1cc accumulation in human cells. The authors identified TEX264 (620608) as a p97 cofactor. TEX264 simultaneously interacted with p97 and TOP1 to form a complex to bridge recruitment of p97 specifically to TOP1cc. TEX264 knockout caused substantial TOP1cc accumulation, which led to significantly delayed DNA damage repair. This phenotype was similar to that of TDP1 (607198) depletion, as TEX264 was epistatic with TDP1 and interacted with TDP1 to promote TOP1cc repair. TEX264 function in TOP1cc repair was mediated by sumoylation. TOP1 was sumoylated, and TEX264, which contains 2 putative SUMO-interacting motifs (SIMs) in its GyrI-like domain, bound to sumoylated TOP1 for its recruitment to TOP1cc. In addition, SPRTN (616086), a metalloprotease that proteolytically cleaves TOP1, contributed to TOP1cc repair. TEX264 associated with SPRTN at the nuclear periphery and acted at replication forks.
Kunze et al. (1991) demonstrated that the coding sequence of TOP1 is split into 21 exons distributed over at least 85 kb of genomic DNA. The sizes of the 20 introns varied between 0.2 and at least 30 kb. Baumgartner et al. (1994) found a similar exon-intron structure in the Top1 gene of the mouse.
Koster et al. (2007) used single-molecule nanomanipulation to monitor the dynamics of human topoisomerase I in the presence of topotecan, a camptothecin. This allowed detection of the binding and unbinding of an individual topotecan molecule in real time and quantification of the drug-induced trapping of topoisomerase on DNA. Unexpectedly, Koster et al. (2007) found that topotecan significantly hindered topoisomerase-mediated DNA uncoiling, with a more pronounced effect on the removal of positive (overwound) versus negative supercoils. In vivo experiments in the budding yeast verified the resulting prediction that positive supercoils would accumulate during transcription and replication as a consequence of camptothecin poisoning of topoisomerase I. Positive supercoils, however, were not induced by drug treatment of cells expressing a catalytically active, camptothecin-resistant topoisomerase I mutant. Koster et al. (2007) concluded that the combination of single-molecule and in vivo data suggested a cytotoxic mechanism for camptothecins, in which the accumulation of positive supercoils ahead of the replication machinery induces potentially lethal DNA lesions.
Juan et al. (1988) mapped the TOP1 gene to 20q12-q13.2 by a combination of in situ hybridization and somatic cell hybridization. They showed that the human TOP1 is a single-copy gene. By Southern blotting of digested DNA from a panel of rodent-human somatic cell hybrids, Kunze et al. (1989) demonstrated that the complete gene is located on chromosome 20 and that 2 truncated pseudogenes are located on chromosomes 1 and 22. In situ hybridization showed that the complete gene is on band 20q11.2-q13.1 and that the pseudogenes are on bands 1q23-q24 and 22q11.2-q13.1.
Baumgartner et al. (1994) mapped the mouse Top1 gene to distal chromosome 2. In addition, the mouse genome contains one truncated processed Top1-related pseudogene on chromosome 16 where, together with the immunoglobulin lambda light chain gene (147220), it defines a conserved linkage group common to murine chromosome 16 and human chromosome 22. The mapping data and structural features suggest that the pseudogene was established before mammalian radiation.
Ahuja et al. (1999) cloned and characterized a t(11;20)(p15;q11) translocation from patients with therapy-related acute myelogenous leukemia (see 601626) and therapy-related myelodysplastic syndromes. They found that the breakpoint on 11p15 targets the NUP98 gene (601021) and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C terminus. The breakpoint on 20q11 occurred within the TOP1 gene. As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of TOP1. Ahuja et al. (1999) concluded that NUP98 is a recurrent target in therapy-related malignancies and that TOP1 is a previously unrecognized target for chromosomal translocations.
Camptothecin (CPT), an alkaloid isolated from the plant Camptotheca acuminata, has a strong antitumor activity against a wide variety of experimental tumors. It is a specific inhibitor of eukaryotic DNA topoisomerase I. Tamura et al. (1991) demonstrated that a CPT-resistant human leukemia cell line had 2 mutations in the TOP1 gene, which caused amino acid changes from aspartic acid to glycine at residues 533 and 583 of the enzyme protein.
Chang et al. (2002) identified a G-to-A transition at nucleotide 1463 of the TOP1 gene, resulting in a glu418-to-lys (E418K) substitution, as the basis of CPT resistance.
Ahuja, H. G., Felix, C. A., Aplan, P. D. The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion. Blood 94: 3258-3261, 1999. [PubMed: 10556215]
Baumgartner, B., Klett, C., Hameister, H., Richter, A., Knippers, R. Mouse genes encoding DNA topoisomerase I. Mammalian Genome 5: 19-25, 1994. [PubMed: 8111124] [Full Text: https://doi.org/10.1007/BF00360563]
Chang, J.-Y., Liu, J.-F., Juang, S.-H., Liu, T.-W., Chen, L.-T. Novel mutation of topoisomerase I in rendering cells resistant to camptothecin. Cancer Res. 62: 3716-3721, 2002. [PubMed: 12097280]
Chu, D. S., Liu, H., Nix, P., Wu, T. F., Ralston, E. J., Yates, J. R., III, Meyer, B. J. Sperm chromatin proteomics identifies evolutionarily conserved fertility factors. Nature 443: 101-105, 2006. [PubMed: 16943775] [Full Text: https://doi.org/10.1038/nature05050]
D'Arpa, P., Machlin, P. S., Ratrie, H., III, Rothfield, N. F., Cleveland, D. W., Earnshaw, W. C. cDNA cloning of human DNA topoisomerase I: catalytic activity of a 67.7-kDa carboxyl-terminal fragment. Proc. Nat. Acad. Sci. 85: 2543-2547, 1988. [PubMed: 2833744] [Full Text: https://doi.org/10.1073/pnas.85.8.2543]
Dejosez, M., Ura, H., Brandt, V. L., Zwaka, T. P. Safeguards for cell cooperation in mouse embryogenesis shown by genome-wide cheater screen. Science 341: 1511-1514, 2013. [PubMed: 24030493] [Full Text: https://doi.org/10.1126/science.1241628]
Fielden, J., Wiseman, K., Torrecilla, I., Li, S., Hume, S., Chiang, S. C., Ruggiano, A., Narayan Singh, A., Freire, R., Hassanieh, S., Domingo, E., Vendrell, I., Fischer, R., Kessler, B. M., Maughan, T. S., El-Khamisy, S. F., Ramadan, K. TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nature Commun. 11: 1274, 2020. [PubMed: 32152270] [Full Text: https://doi.org/10.1038/s41467-020-15000-w]
Humbert, N., Martien, S., Augert, A., Da Costa, M., Mauen, S., Abbadie, C., de Launoit, Y., Gil, J., Bernard, D. A genetic screen identifies topoisomerase 1 as a regulator of senescence. Cancer Res. 69: 4101-4106, 2009. [PubMed: 19435923] [Full Text: https://doi.org/10.1158/0008-5472.CAN-08-2864]
Juan, C.-C., Hwang, J., Liu, A. A., Whang-Peng, J., Knutsen, T., Huebner, K., Croce, C. M., Zhang, H., Wang, J. C., Liu, L. F. Human DNA topoisomerase I is encoded by a single-copy gene that maps to chromosome region 20q12-13.2. Proc. Nat. Acad. Sci. 85: 8910-8913, 1988. [PubMed: 2848244] [Full Text: https://doi.org/10.1073/pnas.85.23.8910]
Kim, N., Huang, S. N., Williams, J. S., Li, Y. C., Clark, A. B., Cho, J.-E., Kunkel, T. A., Pommier, Y., Jinks-Robertson, S. Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332: 1561-1564, 2011. [PubMed: 21700875] [Full Text: https://doi.org/10.1126/science.1205016]
King, I. F., Yandava, C. N., Mabb, A. M., Hsiao, J. S., Huang, H.-S., Pearson, B. L., Calabrese, J. M., Starmer, J., Parker, J. S., Magnuson, T., Chamberlain, S. J., Philpot, B. D., Zylka, M. J. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501: 58-62, 2013. [PubMed: 23995680] [Full Text: https://doi.org/10.1038/nature12504]
Koster, D. A., Croquette, V., Dekker, C., Shuman, S., Dekker, N. H. Friction and torque govern the relaxation of DNA supercoils by eukaryotic topoisomerase IB. Nature 434: 671-674, 2005. [PubMed: 15800630] [Full Text: https://doi.org/10.1038/nature03395]
Koster, D. A., Palle, K., Bot, E. S. M., Bjornsti, M.-A., Dekker, N. H. Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448: 213-217, 2007. [PubMed: 17589503] [Full Text: https://doi.org/10.1038/nature05938]
Kunze, N., Yang, G. C., Jiang, Z. Y., Hameister, H., Adolph, S., Wiedorn, K.-H., Richter, A., Knippers, R. Localization of the active type I DNA topoisomerase gene on human chromosome 20q11.2-13.1, and two pseudogenes on chromosomes 1q23-24 and 22q11.2-13.1. Hum. Genet. 84: 6-10, 1989. [PubMed: 2558068] [Full Text: https://doi.org/10.1007/BF00210661]
Kunze, N., Yang, G., Dolberg, M., Sundarp, R., Knippers, R., Richter, A. Structure of the human type I DNA topoisomerase gene. J. Biol. Chem. 266: 9610-9616, 1991. [PubMed: 1851751]
Tamura, H., Kohchi, C., Yamada, R., Ikeda, T., Koiwai, O., Patterson, E., Keene, J. D., Okada, K., Kjeldsen, E., Nishikawa, K., Andoh, T. Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites. Nucleic Acids Res. 19: 69-75, 1991. [PubMed: 1849260] [Full Text: https://doi.org/10.1093/nar/19.1.69]