TOP3A

DNA topoisomerase 3-alpha is an enzyme that in humans is encoded by the TOP3A gene.[5][6]

TOP3A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4CGY, 4CHT
Identifiers
Aliases	TOP3A, TOP3, ZGRF7, topoisomerase (DNA) III alpha, DNA topoisomerase III alpha, PEOB5, MGRISCE2
External IDs	OMIM: 601243 MGI: 1197527 HomoloGene: 3394 GeneCards: TOP3A
Gene location (Human) Chr. Chromosome 17 (human)[1] Band 17p11.2 Start 18,271,428 bp[1] End 18,315,007 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B2 Start 60,740,058 bp[2] End 60,777,365 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA topoisomerase type I activity • DNA binding • zinc ion binding • GO:0001948 protein binding • isomerase activity • metal ion binding • DNA topoisomerase activity • single-stranded DNA binding • nucleic acid binding Cellular component • PML body • nucleoplasm • chromosome • cell nucleus • mitochondrion • mitochondrial matrix Biological process • DNA replication • DNA topological change • GO:0007126 meiotic cell cycle • mitochondrial DNA metabolic process • chromosome separation • regulation of signal transduction by p53 class mediator Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7156	21975
Ensembl	ENSG00000284238 ENSG00000177302	ENSMUSG00000002814
UniProt	Q13472	O70157
RefSeq (mRNA)	NM_004618 NM_001320759	NM_009410
RefSeq (protein)	NP_001307688 NP_004609	NP_033436
Location (UCSC)	Chr 17: 18.27 – 18.32 Mb	Chr 11: 60.74 – 60.78 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 allows the strands to pass through one another, thus reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells.[6]

Meiosis

A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

Recombination during meiosis is often initiated by a DNA double-strand break (DSB). During recombination, sections of DNA at the 5' ends of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" the DNA of an homologous chromosome that is not broken forming a displacement loop (D-loop). After strand invasion, the further sequence of events may follow either of two main pathways leading to a crossover (CO) or a non-crossover (NCO) recombinant (see Genetic recombination and see Figure). The pathway leading to a NCO is referred to as Synthesis-dependent strand annealing (SDSA).

In the plant Arabidopsis thaliana, multiple mechanisms limit meiotic COs.[7] During meiosis TOP3A and RECQ4A/B helicase antagonize formation of COs in parallel to FANCM helicase.[7] Sequela-Arnaud et al.[7] suggested that CO numbers are restricted because of the long-term costs of CO recombination, that is, the breaking up of favorable genetic combinations of alleles built up by past natural selection.

In the budding yeast Saccharomyces cerevisiae, the topoisomerase III (TOP3)-RMI1 heterodimer (that catalyzes DNA single-strand passage) forms a conserved complex with Sgs1 helicase (an ortholog of the human Bloom syndrome helicase). This complex promotes early formation of NCO recombinants during meiosis[8] The TOP3-RMI1 strand passage activity appears to have two important functions during meiosis.[8] First, strand passage activity is employed early in coordination with Sgs1 helicase to promote proper recombination pathway choice. Second, strand passage activity is used later, independently of Sgs1 helicase, to prevent the persistence of unresolvable strand entanglements in recombination intermediates.

Interactions

TOP3A has been shown to interact with Bloom syndrome protein.[9][10][11][12]

References

1. ENSG00000177302 GRCh38: Ensembl release 89: ENSG00000284238, ENSG00000177302 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000002814 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Elsea SH, Fritz E, Schoener-Scott R, Meyn MS, Patel PI (Jan 1998). "Gene for topoisomerase III maps within the Smith-Magenis syndrome critical region: analysis of cell-cycle distribution and radiation sensitivity". American Journal of Medical Genetics. 75 (1): 104–8. doi:10.1002/(SICI)1096-8628(19980106)75:1<104::AID-AJMG21>3.0.CO;2-P. PMID 9450867.
6. "Entrez Gene: TOP3A topoisomerase (DNA) III alpha".
7. Séguéla-Arnaud M, Crismani W, Larchevêque C, Mazel J, Froger N, Choinard S, Lemhemdi A, Macaisne N, Van Leene J, Gevaert K, De Jaeger G, Chelysheva L, Mercier R (Apr 2015). "Multiple mechanisms limit meiotic crossovers: TOP3α and two BLM homologs antagonize crossovers in parallel to FANCM". Proceedings of the National Academy of Sciences of the United States of America. 112 (15): 4713–8. doi:10.1073/pnas.1423107112. PMC 4403193. PMID 25825745.
8. Kaur H, De Muyt A, Lichten M (Feb 2015). "Top3-Rmi1 DNA single-strand decatenase is integral to the formation and resolution of meiotic recombination intermediates". Molecular Cell. 57 (4): 583–94. doi:10.1016/j.molcel.2015.01.020. PMC 4338413. PMID 25699707.
9. Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (Mar 2000). "The Bloom's syndrome gene product interacts with topoisomerase III". The Journal of Biological Chemistry. 275 (13): 9636–44. doi:10.1074/jbc.275.13.9636. PMID 10734115.
10. Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (Aug 2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha". Nucleic Acids Research. 29 (15): 3172–80. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874.
11. Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (Jun 2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Human Molecular Genetics. 10 (12): 1287–98. doi:10.1093/hmg/10.12.1287. PMID 11406610.
12. Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (Aug 2000). "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". The Journal of Biological Chemistry. 275 (31): 23500–8. doi:10.1074/jbc.M001557200. PMID 10825162.

Further reading

• Hanai R, Caron PR, Wang JC (Apr 1996). "Human TOP3: a single-copy gene encoding DNA topoisomerase III". Proceedings of the National Academy of Sciences of the United States of America. 93 (8): 3653–7. doi:10.1073/pnas.93.8.3653. PMC 39666. PMID 8622991.
• Fritz E, Elsea SH, Patel PI, Meyn MS (Apr 1997). "Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype". Proceedings of the National Academy of Sciences of the United States of America. 94 (9): 4538–42. doi:10.1073/pnas.94.9.4538. PMC 20758. PMID 9114025.
• Kim JC, Yoon JB, Koo HS, Chung IK (Oct 1998). "Cloning and characterization of the 5'-flanking region for the human topoisomerase III gene". The Journal of Biological Chemistry. 273 (40): 26130–7. doi:10.1074/jbc.273.40.26130. PMID 9748294.
• Goulaouic H, Roulon T, Flamand O, Grondard L, Lavelle F, Riou JF (Jun 1999). "Purification and characterization of human DNA topoisomerase IIIalpha". Nucleic Acids Research. 27 (12): 2443–50. doi:10.1093/nar/27.12.2443. PMC 148446. PMID 10352172.
• Shimamoto A, Nishikawa K, Kitao S, Furuichi Y (Apr 2000). "Human RecQ5beta, a large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and interacts with topoisomerases 3alpha and 3beta". Nucleic Acids Research. 28 (7): 1647–55. doi:10.1093/nar/28.7.1647. PMC 102787. PMID 10710432.
• Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID (Mar 2000). "The Bloom's syndrome gene product interacts with topoisomerase III". The Journal of Biological Chemistry. 275 (13): 9636–44. doi:10.1074/jbc.275.13.9636. PMID 10734115.
• Lin CW, Darzynkiewicz Z, Li X, Traganos F, Bedner E, Tse-Dinh YC (Apr 2000). "Differential expression of human topoisomerase IIIalpha during the cell cycle progression in HL-60 leukemia cells and human peripheral blood lymphocytes". Experimental Cell Research. 256 (1): 225–36. doi:10.1006/excr.1999.4778. PMID 10739669.
• Brosh RM, Li JL, Kenny MK, Karow JK, Cooper MP, Kureekattil RP, Hickson ID, Bohr VA (Aug 2000). "Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity". The Journal of Biological Chemistry. 275 (31): 23500–8. doi:10.1074/jbc.M001557200. PMID 10825162.
• Lodge AJ, Anderson JJ, Ng SW, Fenwick F, Steward M, Haugk B, Horne CH, Angus B (Aug 2000). "Expression of topoisomerase IIIalpha in normal and neoplastic tissues determined by immunohistochemistry using a novel monoclonal antibody". British Journal of Cancer. 83 (4): 498–505. doi:10.1054/bjoc.2000.1293. PMC 2374664. PMID 10945498.
• Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA (Jun 2001). "Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability". Human Molecular Genetics. 10 (12): 1287–98. doi:10.1093/hmg/10.12.1287. PMID 11406610.
• Freire R, d'Adda Di Fagagna F, Wu L, Pedrazzi G, Stagljar I, Hickson ID, Jackson SP (Aug 2001). "Cleavage of the Bloom's syndrome gene product during apoptosis by caspase-3 results in an impaired interaction with topoisomerase IIIalpha". Nucleic Acids Research. 29 (15): 3172–80. doi:10.1093/nar/29.15.3172. PMC 55826. PMID 11470874.
• Bi W, Yan J, Stankiewicz P, Park SS, Walz K, Boerkoel CF, Potocki L, Shaffer LG, Devriendt K, Nowaczyk MJ, Inoue K, Lupski JR (May 2002). "Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse". Genome Research. 12 (5): 713–28. doi:10.1101/gr.73702. PMC 186594. PMID 11997338.
• Wang Y, Lyu YL, Wang JC (Sep 2002). "Dual localization of human DNA topoisomerase IIIalpha to mitochondria and nucleus". Proceedings of the National Academy of Sciences of the United States of America. 99 (19): 12114–9. doi:10.1073/pnas.192449499. PMC 129407. PMID 12209014.
• Wu L, Hickson ID (Nov 2002). "The Bloom's syndrome helicase stimulates the activity of human topoisomerase IIIalpha". Nucleic Acids Research. 30 (22): 4823–9. doi:10.1093/nar/gkf611. PMC 137159. PMID 12433984.
• Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W (Oct 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351.
• Jiao R, Bachrati CZ, Pedrazzi G, Kuster P, Petkovic M, Li JL, Egli D, Hickson ID, Stagljar I (Jun 2004). "Physical and functional interaction between the Bloom's syndrome gene product and the largest subunit of chromatin assembly factor 1". Molecular and Cellular Biology. 24 (11): 4710–9. doi:10.1128/MCB.24.11.4710-4719.2004. PMC 416397. PMID 15143166.
• Yin J, Sobeck A, Xu C, Meetei AR, Hoatlin M, Li L, Wang W (Apr 2005). "BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity". The EMBO Journal. 24 (7): 1465–76. doi:10.1038/sj.emboj.7600622. PMC 1142546. PMID 15775963.